Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: PTEN nuclear localization is well-established. Nuclear PTEN has distinct roles in genomic stability, DNA damage response, and cell cycle control, regulated by PTMs and ubiquitin-dependent trafficking. Reason: Nuclear localization is a conserved and functionally important feature of PTEN, supported by extensive experimental evidence and phylogenetic conservation. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner PMID:17218261 Ubiquitination regulates PTEN nuclear import and tumor suppression file:human/PTEN/PTEN-deep-research-falcon.md See deep research file for comprehensive analysis
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Plasma membrane localization is essential for PTEN's core lipid phosphatase function. PTEN is recruited to the membrane via its C2 domain and PDZ-binding motif interactions with scaffold proteins like MAGI-2. Reason: Plasma membrane localization is the primary site of PTEN's lipid phosphatase activity against PIP3, essential for its tumor suppressor function. Supporting Evidence: PMID:10760291 PTEN binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-2 enhances the ability of PTEN to suppress Akt activation.
GO:0042995 cell projection	IBA GO_REF:0000033	ACCEPT	Summary: PTEN localizes to cell projections, consistent with its role in regulating cell motility through PI3K signaling modulation at the leading edge of cells. Reason: PTEN localization to cell projections is consistent with its role in regulating directed cell migration through local PIP3 levels, a phylogenetically conserved feature.
GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: PTEN is a central component of PI3K/AKT signaling, acting as the primary negative regulator by dephosphorylating PIP3 to PIP2. Reason: This is the core pathway in which PTEN functions. By removing PIP3, PTEN prevents AKT recruitment and activation, making this a core annotation. Supporting Evidence: PMID:9811831 ectopic expression of the phosphatase in PTEN-deficient tumor cell lines resulted in the inhibition of protein kinase (PK) B/Akt and regulation of cell survival
GO:0051896 regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IBA GO_REF:0000033	MODIFY	Summary: PTEN negatively regulates PI3K/AKT signaling via its lipid phosphatase activity. This is redundant with GO:0051898 (negative regulation) which is more specific. Reason: While accurate, GO:0051898 (negative regulation of PI3K/AKT signaling) is more specific to PTEN's actual role as an antagonist of this pathway. Proposed replacements: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: PTEN is found in the cytosol where it can exist in an inactive closed conformation. Cytosolic PTEN can be recruited to membranes for its lipid phosphatase function. Reason: Cytosolic localization is well-established for PTEN and represents a reservoir pool that can be recruited to membranes upon appropriate signals.
GO:0046856 phosphatidylinositol dephosphorylation	IBA GO_REF:0000033	ACCEPT	Summary: PTEN dephosphorylates phosphatidylinositols at the D3 position, with primary activity against PIP3 and PI(3,4)P2. Reason: This is a core biological process annotation that accurately describes PTEN's primary enzymatic function. Supporting Evidence: PMID:9811831 Characterization of the lipid phosphatase activity of PTEN demonstrates that it shows specificity for phosphatidylinositols phosphorylated at the 3 position.
GO:0004725 protein tyrosine phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: PTEN exhibits protein tyrosine phosphatase activity as part of its dual-specificity phosphatase function, though the lipid phosphatase activity is the critical determinant of tumor suppression. Reason: PTEN has documented protein tyrosine phosphatase activity. While secondary to its lipid phosphatase function for tumor suppression, this is a legitimate enzymatic activity. Supporting Evidence: PMID:9256433 recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues, indicating that P-TEN is a dual-specificity phosphatase
GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: This is PTEN's primary enzymatic activity - dephosphorylating PIP3 at the D3 position to produce PIP2. This activity is essential for its tumor suppressor function. Reason: This is the core molecular function of PTEN. The lipid phosphatase activity against PIP3 is the critical determinant of PTEN's tumor suppressor function. Supporting Evidence: PMID:9811831 a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease
GO:0048870 cell motility	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: PTEN regulates cell motility through its effects on PIP3 levels, which control cell polarity and directed migration. Loss of PTEN enhances cell motility. Reason: While PTEN's regulation of cell motility is well-established, this is a downstream effect of its lipid phosphatase activity rather than a core function. The core function is PIP3 dephosphorylation. Supporting Evidence: PMID:9616126 Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN
GO:0004722 protein serine/threonine phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: PTEN has dual-specificity protein phosphatase activity including activity against serine/threonine residues. Reason: This is supported by experimental evidence showing PTEN dephosphorylates serine/threonine substrates. Supporting Evidence: PMID:9256433 recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues
GO:0004725 protein tyrosine phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation for the same term. PTEN has documented protein tyrosine phosphatase activity. Reason: Consistent with experimental evidence for PTEN's dual-specificity phosphatase activity.
GO:0004721 phosphoprotein phosphatase activity	IEA GO_REF:0000043	ACCEPT	Summary: General phosphoprotein phosphatase activity term. PTEN does have protein phosphatase activity but more specific terms (GO:0004722, GO:0004725) are preferred. Reason: Accurate but less specific than existing annotations. Still valid as a parent term.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: PTEN-Long (PTEN-L/alpha) isoform can be secreted and taken up by other cells. This applies specifically to the N-terminally extended isoform. Reason: The PTEN-L isoform has been shown to be secreted and function in neighboring cells (PMID:23744781). Supporting Evidence: PMID:23744781 A secreted PTEN phosphatase that enters cells to alter signaling and survival
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate of IBA annotation. Nuclear localization of PTEN is well-established. Reason: Consistent with IBA annotation and extensive experimental evidence for nuclear PTEN.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: PTEN is found in the cytoplasm. Cytosol (GO:0005829) is a more specific term that is also annotated. Reason: Cytoplasmic localization is accurate, though cytosol is the more specific subcellular location.
GO:0006629 lipid metabolic process	IEA GO_REF:0000043	MODIFY	Summary: Very broad term. PTEN dephosphorylates phosphatidylinositols but this is more accurately described as phosphatidylinositol dephosphorylation (GO:0046856). Reason: Too general. GO:0046856 (phosphatidylinositol dephosphorylation) is much more specific and accurate for PTEN's function. Proposed replacements: phosphatidylinositol dephosphorylation
GO:0006915 apoptotic process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: PTEN promotes apoptosis by inhibiting PI3K/AKT survival signaling. This is a downstream effect of PTEN's lipid phosphatase activity rather than a direct function. Reason: Apoptosis regulation is a downstream consequence of PTEN's inhibition of AKT survival signaling, not a direct molecular function. Supporting Evidence: PMID:9811831 ectopic expression of the phosphatase in PTEN-deficient tumor cell lines resulted in the inhibition of protein kinase (PK) B/Akt and regulation of cell survival
GO:0007399 nervous system development	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: PTEN plays important roles in nervous system development by regulating neuron size, dendritic arborization, and synapse formation through PI3K/AKT/mTOR signaling. Reason: While PTEN has well-documented roles in nervous system development (PTEN mutations cause macrocephaly and autism spectrum disorders), this is a pleiotropic effect of its core lipid phosphatase function.
GO:0008285 negative regulation of cell population proliferation	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: PTEN suppresses cell proliferation through its antagonism of PI3K/AKT/mTOR signaling. This is a key aspect of its tumor suppressor function. Reason: While this is a fundamental consequence of PTEN function and central to its tumor suppressor role, it is a downstream effect of PI3K/AKT pathway inhibition rather than a direct molecular function. Supporting Evidence: PMID:10468583 The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region
GO:0008289 lipid binding	IEA GO_REF:0000043	ACCEPT	Summary: PTEN binds phosphatidylinositol lipids as substrates via its C2 domain and phosphatase domain. Reason: PTEN's C2 domain mediates membrane/lipid binding which is essential for its localization and function.
GO:0009966 regulation of signal transduction	IEA GO_REF:0000117	MODIFY	Summary: Very broad term. PTEN specifically regulates PI3K/AKT signal transduction via its lipid phosphatase activity. Reason: Too general. GO:0051898 (negative regulation of PI3K/AKT signaling) is more specific and accurate. Proposed replacements: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
GO:0010604 positive regulation of macromolecule metabolic process	IEA GO_REF:0000117	REMOVE	Summary: Very broad and vague term with unclear relationship to PTEN's core functions. PTEN actually inhibits anabolic processes by suppressing mTOR signaling. Reason: This annotation is too vague and potentially misleading. PTEN generally suppresses anabolic metabolism through mTOR inhibition rather than promoting macromolecule metabolism.
GO:0010648 negative regulation of cell communication	IEA GO_REF:0000117	MODIFY	Summary: Very broad term. PTEN specifically inhibits PI3K/AKT signaling. Reason: Too general. GO:0051898 (negative regulation of PI3K/AKT signaling) is the specific pathway PTEN regulates. Proposed replacements: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation. This is PTEN's primary enzymatic activity. Reason: Consistent with IBA annotation and extensive experimental evidence. This is the core molecular function of PTEN.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: Very broad parent term for PTEN's phosphatase activities. Reason: While very general, this is technically accurate as a parent term of phosphatase activity.
GO:0016791 phosphatase activity	IEA GO_REF:0000002	ACCEPT	Summary: General phosphatase activity term. More specific terms for lipid and protein phosphatase activities are preferred. Reason: Accurate as a parent term, though more specific annotations exist.
GO:0019899 enzyme binding	IEA GO_REF:0000117	ACCEPT	Summary: PTEN binds multiple enzymes including kinases and ubiquitin ligases that regulate its activity and stability. Reason: PTEN interacts with various enzymes for regulation of its activity, localization, and stability.
GO:0023057 negative regulation of signaling	IEA GO_REF:0000117	MODIFY	Summary: Broad term. PTEN specifically negatively regulates PI3K/AKT signaling. Reason: Too general. GO:0051898 (negative regulation of PI3K/AKT signaling) is more specific. Proposed replacements: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
GO:0030351 inositol-1,3,4,5,6-pentakisphosphate 3-phosphatase activity	IEA GO_REF:0000116	ACCEPT	Summary: PTEN can dephosphorylate soluble inositol phosphates in addition to phosphatidylinositol lipids. Reason: This activity has been demonstrated experimentally (PMID:11418101). Supporting Evidence: PMID:11418101 Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity
GO:0045595 regulation of cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: PTEN affects cell differentiation through PI3K/AKT/mTOR pathway modulation. Reason: This is a downstream pleiotropic effect of PTEN's lipid phosphatase activity, not a core function.
GO:0046856 phosphatidylinositol dephosphorylation	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. Core biological process for PTEN. Reason: Consistent with IBA annotation. This is a core process term for PTEN's primary function.
GO:0051093 negative regulation of developmental process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Very broad term. PTEN affects development through PI3K/AKT pathway regulation. Reason: Downstream pleiotropic effect of PTEN's lipid phosphatase activity. Too general to be informative.
GO:0051129 negative regulation of cellular component organization	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Very broad term with unclear mechanistic connection to PTEN's core functions. Reason: This is too vague and likely an over-annotation. PTEN's effects on cellular organization are indirect consequences of PI3K/AKT signaling modulation.
GO:0051241 negative regulation of multicellular organismal process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Very broad term with unclear mechanistic basis. Reason: Too vague to be informative. This is an indirect consequence of PTEN's lipid phosphatase activity.
GO:0051717 inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: PTEN can dephosphorylate soluble inositol polyphosphates including I(1,3,4,5)P4. Reason: This activity has been demonstrated experimentally (PMID:9593664). Supporting Evidence: PMID:9593664 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
GO:0051726 regulation of cell cycle	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: PTEN regulates cell cycle through multiple mechanisms including AKT-mediated effects on p27/p21 and nuclear PTEN effects on APC/CDH1. Reason: While PTEN has well-documented effects on cell cycle, these are downstream of its lipid phosphatase activity and nuclear functions, not a primary molecular function. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner
GO:0051800 phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity	IEA GO_REF:0000002	ACCEPT	Summary: PTEN can dephosphorylate PI(3,4)P2 in addition to PIP3, though PIP3 is the primary substrate. Reason: This is a documented enzymatic activity of PTEN (PMID:9811831). Supporting Evidence: PMID:9811831 Characterization of the lipid phosphatase activity of PTEN demonstrates that it shows specificity for phosphatidylinositols phosphorylated at the 3 position
GO:0005515 protein binding	IPI PMID:15951562 Binding of PTEN to specific PDZ domains contributes to PTEN ...	MODIFY	Summary: PTEN binds PDZ domain-containing proteins (MAGI2, MAGI3, MAST1, MAST2, MAST3) through its C-terminal PDZ-binding motif. Reason: Generic protein binding is uninformative. GO:0030165 (PDZ domain binding) is more specific and accurate for this interaction. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:15951562 Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases
GO:0005515 protein binding	IPI PMID:16456542 PTEN tumor suppressor associates with NHERF proteins to atte...	MODIFY	Summary: PTEN associates with NHERF proteins to attenuate PDGF receptor signaling. Reason: Generic protein binding is uninformative. More specific term for NHERF/PDZ scaffold binding is preferred. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:16456542 PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling.
GO:0005515 protein binding	IPI PMID:17274640 A limited screen for protein interactions reveals new roles ...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with protein phosphatase 1. Reason: Generic protein binding is uninformative. More specific binding terms should be used when the interacting partner is known. Supporting Evidence: PMID:17274640 A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis.
GO:0005515 protein binding	IPI PMID:19345329 Rak functions as a tumor suppressor by regulating PTEN prote...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with FRK kinase which phosphorylates and stabilizes PTEN. Reason: Generic protein binding is uninformative. The specific interaction with FRK kinase is relevant for PTEN regulation but would be better annotated with a kinase binding term. Supporting Evidence: PMID:19345329 Rak functions as a tumor suppressor by regulating PTEN protein stability and function.
GO:0005515 protein binding	IPI PMID:19369943 Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activit...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with peroxiredoxin 1 (Prdx1) which regulates PTEN oxidation. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:19369943 Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity.
GO:0005515 protein binding	IPI PMID:19903340 PTEN inhibits BMI1 function independently of its phosphatase...	MARK AS OVER ANNOTATED	Summary: PTEN inhibits BMI1 function independently of its phosphatase activity. Reason: Generic protein binding is uninformative. This interaction represents a non-canonical PTEN function. Supporting Evidence: PMID:19903340 PTEN inhibits BMI1 function independently of its phosphatase activity.
GO:0005515 protein binding	IPI PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	MODIFY	Summary: Nuclear PTEN interacts with the APC-CDH1 complex. Reason: More specific term should be used. GO:0010997 (anaphase-promoting complex binding) is appropriate. Proposed replacements: anaphase-promoting complex binding Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	MARK AS OVER ANNOTATED	Summary: High-throughput study of protein interactions in autism spectrum disorders. Reason: Generic protein binding from high-throughput study is uninformative without specific interactor information. Supporting Evidence: PMID:21653829 Protein interactome reveals converging molecular pathways among autism disorders.
GO:0005515 protein binding	IPI PMID:21804599 PTEN, NHERF1 and PHLPP form a tumor suppressor network that ...	MARK AS OVER ANNOTATED	Summary: PTEN forms a tumor suppressor network with NHERF1 and PHLPP. Reason: Generic protein binding is uninformative. Specific scaffold/adapter binding terms would be more appropriate. Supporting Evidence: PMID:21804599 PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma.
GO:0005515 protein binding	IPI PMID:23514585 PTEN suppresses the oncogenic function of AIB1 through decre...	MARK AS OVER ANNOTATED	Summary: PTEN suppresses oncogenic AIB1 by promoting its degradation via Fbw7. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:23514585 PTEN suppresses the oncogenic function of AIB1 through decreasing its protein stability via mechanism involving Fbw7 alpha.
GO:0005515 protein binding	IPI PMID:23940795 Phosphorylation of the actin binding protein Drebrin at S647...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with drebrin and regulates its phosphorylation. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:23940795 Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN.
GO:0005515 protein binding	IPI PMID:24012959 Breast cancer-derived K172N, D301V mutations abolish Na+/H+ ...	MODIFY	Summary: PTEN interacts with NHERF1 which regulates PDGF receptor signaling. Reason: Generic protein binding is uninformative. GO:0030165 (PDZ domain binding) is more specific. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:24012959 Epub 2013 Sep 5. Breast cancer-derived K172N, D301V mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of platelet-derived growth factor receptor signaling.
GO:0005515 protein binding	IPI PMID:24656772 SPOP promotes tumorigenesis by acting as a key regulatory hu...	MARK AS OVER ANNOTATED	Summary: PTEN is a substrate of SPOP ubiquitin ligase. Reason: Generic protein binding is uninformative. This represents PTEN regulation by ubiquitination. Supporting Evidence: PMID:24656772 2014 Mar 20. SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: High-throughput proximity ligation assay study. Reason: Generic protein binding from high-throughput study is uninformative. Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
GO:0005515 protein binding	IPI PMID:36950384 Protein interaction studies in human induced neurons indicat...	MARK AS OVER ANNOTATED	Summary: Protein interaction study in neurons related to autism. Reason: Generic protein binding from high-throughput study is uninformative. Supporting Evidence: PMID:36950384 eCollection 2023 Mar 8.
GO:0042802 identical protein binding	IPI PMID:24766807 Cancer-associated PTEN mutants act in a dominant-negative ma...	ACCEPT	Summary: Cancer-associated PTEN mutants can act in a dominant-negative manner by binding to wild-type PTEN, suggesting PTEN dimerization. Reason: PTEN homodimerization is documented and may be relevant for its regulation and for dominant-negative effects of cancer mutations. Supporting Evidence: PMID:24766807 Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function
GO:0006661 phosphatidylinositol biosynthetic process	TAS Reactome:R-HSA-1660499	MODIFY	Summary: PTEN is involved in phosphatidylinositol metabolism by dephosphorylating 3-phosphorylated phosphoinositides, but this is catabolism not biosynthesis. Reason: PTEN dephosphorylates phosphoinositides (catabolic), not biosynthesis. GO:0046856 (phosphatidylinositol dephosphorylation) is more accurate. Proposed replacements: phosphatidylinositol dephosphorylation
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	TAS Reactome:R-HSA-199456	ACCEPT	Summary: PTEN negatively regulates PI3K/AKT signaling by dephosphorylating PIP3. This is a core process annotation. Reason: This is the primary biological process in which PTEN functions. Core annotation. Supporting Evidence: PMID:9811831 PTEN functions to suppress these growth-promoting and survival signals by dephosphorylating the phospholipid products of PI 3-kinase
GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity	TAS Reactome:R-HSA-199456	ACCEPT	Summary: PTEN's primary enzymatic activity. Duplicate of IBA and IDA annotations. Reason: Core molecular function of PTEN. Essential for tumor suppression.
GO:0008013 beta-catenin binding	IPI PMID:20123964 Lipid phosphate phosphatase 3 stabilization of beta-catenin ...	UNDECIDED	Summary: PTEN can interact with beta-catenin, potentially regulating Wnt signaling. Reason: The reference PMID:20123964 is about lipid phosphate phosphatase 3 (LPP3), not PTEN directly. Need to verify if this annotation is correctly assigned. Supporting Evidence: PMID:20123964 Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:20123964 Lipid phosphate phosphatase 3 stabilization of beta-catenin ...	UNDECIDED	Summary: This annotation appears to be from a study on LPP3, not PTEN directly. Reason: Need to verify reference relevance. PMID:20123964 title is about LPP3, not PTEN. Supporting Evidence: PMID:20123964 Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
GO:0051800 phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity	IDA PMID:20123964 Lipid phosphate phosphatase 3 stabilization of beta-catenin ...	ACCEPT	Summary: PI(3,4)P2 3-phosphatase activity is documented for PTEN, but this reference appears to be about LPP3. Reason: This activity is well-documented for PTEN (PMID:9811831), though the reference may need correction. Supporting Evidence: PMID:20123964 Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
GO:1902533 positive regulation of intracellular signal transduction	IMP PMID:20123964 Lipid phosphate phosphatase 3 stabilization of beta-catenin ...	UNDECIDED	Summary: This annotation appears misattributed. PTEN generally negatively regulates signaling. Reason: PTEN typically inhibits signaling via PI3K/AKT pathway. This positive regulation annotation may be incorrectly assigned or context-specific. Supporting Evidence: PMID:20123964 Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: PTEN localizes to the nucleoplasm where it has phosphatase-independent functions in genomic stability and chromatin regulation. Reason: Nuclear PTEN is well-documented with important functions including interaction with APC-CDH1 and regulation of genomic stability.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: PTEN is present in the cytosol where it can function as both lipid and protein phosphatase Reason: Cytosolic localization allows PTEN to regulate multiple signaling pathways beyond membrane-associated functions
GO:0005886 plasma membrane	IDA PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a me...	ACCEPT	Summary: PTEN localizes to the plasma membrane where it dephosphorylates PIP3 to antagonize PI3K signaling Reason: Plasma membrane localization is essential for PTEN's core lipid phosphatase function against PIP3 Supporting Evidence: PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.
GO:0030351 inositol-1,3,4,5,6-pentakisphosphate 3-phosphatase activity	IDA PMID:11418101 Expanding coincident signaling by PTEN through its inositol ...	ACCEPT	Summary: PTEN can dephosphorylate soluble inositol polyphosphates. This is a secondary enzymatic activity. Reason: This activity is documented experimentally in the cited reference. Supporting Evidence: PMID:11418101 Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity
GO:0045668 negative regulation of osteoblast differentiation	IDA PMID:22869525 Insulin-like growth factor (IGF) binding protein 2 functions...	KEEP AS NON CORE	Summary: PTEN regulates osteoblast differentiation through PI3K/AKT pathway modulation. Reason: This is a tissue-specific downstream effect of PTEN's lipid phosphatase activity, not a core function. Supporting Evidence: PMID:22869525 Aug 6. Insulin-like growth factor (IGF) binding protein 2 functions coordinately with receptor protein tyrosine phosphatase β and the IGF-I receptor to regulate IGF-I-stimulated signaling.
GO:0051800 phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity	TAS Reactome:R-HSA-1676149	ACCEPT	Summary: PI(3,4)P2 3-phosphatase activity is documented for PTEN. Duplicate of IEA annotation. Reason: This is a documented enzymatic activity of PTEN (PMID:9811831).
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	ISS GO_REF:0000024	ACCEPT	Summary: Core process annotation for PTEN. Duplicate of TAS/IDA annotations. Reason: This is the primary biological process in which PTEN functions.
GO:0007270 neuron-neuron synaptic transmission	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects synaptic transmission through PI3K/AKT pathway modulation in neurons. Reason: Downstream tissue-specific effect. PTEN mutations cause neurological phenotypes including autism spectrum disorders.
GO:0007611 learning or memory	ISS PMID:16675393 Pten regulates neuronal arborization and social interaction ...	KEEP AS NON CORE	Summary: PTEN deletion in mouse neurons affects learning and memory through PI3K/mTOR pathway dysregulation. Reason: Downstream pleiotropic effect based on mouse studies. Not a core molecular function. Supporting Evidence: PMID:16675393 Pten regulates neuronal arborization and social interaction in mice.
GO:0007626 locomotory behavior	ISS PMID:16675393 Pten regulates neuronal arborization and social interaction ...	KEEP AS NON CORE	Summary: Neuronal PTEN deletion affects locomotory behavior in mouse studies. Reason: Downstream behavioral effect. Very distant from PTEN's core lipid phosphatase function. Supporting Evidence: PMID:16675393 Pten regulates neuronal arborization and social interaction in mice.
GO:0021542 dentate gyrus development	ISS PMID:17706614 A seizure-prone phenotype is associated with altered free-ru...	KEEP AS NON CORE	Summary: PTEN regulates dentate gyrus development via PI3K/AKT pathway. Reason: Tissue-specific developmental effect. Not a core function. Supporting Evidence: PMID:17706614 2007 Jul 20. A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice.
GO:0021955 central nervous system neuron axonogenesis	ISS PMID:16675393 Pten regulates neuronal arborization and social interaction ...	KEEP AS NON CORE	Summary: PTEN regulates axon growth through PI3K/mTOR signaling. Reason: Downstream effect on neuronal development. Not a core function. Supporting Evidence: PMID:16675393 Pten regulates neuronal arborization and social interaction in mice.
GO:0030534 adult behavior	ISS PMID:16675393 Pten regulates neuronal arborization and social interaction ...	MARK AS OVER ANNOTATED	Summary: PTEN affects adult behavior through neuronal PI3K/AKT signaling. Reason: Too vague and distant from core molecular function. Over-annotation. Supporting Evidence: PMID:16675393 Pten regulates neuronal arborization and social interaction in mice.
GO:0032286 central nervous system myelin maintenance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects myelination through PI3K/AKT/mTOR signaling. Reason: Cell type-specific effect. Not a core function.
GO:0035176 social behavior	ISS PMID:16675393 Pten regulates neuronal arborization and social interaction ...	MARK AS OVER ANNOTATED	Summary: PTEN deletion in neurons affects social behavior (autism-like phenotypes). Reason: Behavioral phenotype very distant from core molecular function. Supporting Evidence: PMID:16675393 Pten regulates neuronal arborization and social interaction in mice.
GO:0042711 maternal behavior	ISS PMID:16675393 Pten regulates neuronal arborization and social interaction ...	MARK AS OVER ANNOTATED	Summary: PTEN affects maternal behavior through neuronal functions. Reason: Behavioral phenotype very distant from core molecular function. Supporting Evidence: PMID:16675393 Pten regulates neuronal arborization and social interaction in mice.
GO:0043005 neuron projection	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN localizes to and regulates neuron projections. Reason: Cell type-specific localization. Valid but not a core function.
GO:0045475 locomotor rhythm	ISS PMID:17706614 A seizure-prone phenotype is associated with altered free-ru...	MARK AS OVER ANNOTATED	Summary: PTEN affects locomotor rhythms through circadian/neuronal mechanisms. Reason: Very indirect behavioral effect. Supporting Evidence: PMID:17706614 2007 Jul 20. A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice.
GO:0045792 negative regulation of cell size	ISS PMID:21411674 Pten knockdown in vivo increases excitatory drive onto denta...	KEEP AS NON CORE	Summary: PTEN suppresses cell growth/size through PI3K/mTOR inhibition. Reason: Well-documented downstream effect but not a core molecular function. Supporting Evidence: PMID:21411674 Pten knockdown in vivo increases excitatory drive onto dentate granule cells.
GO:0046621 negative regulation of organ growth	ISS PMID:19208814 Haploinsufficiency for Pten and Serotonin transporter cooper...	KEEP AS NON CORE	Summary: PTEN suppresses organ growth via PI3K/AKT/mTOR pathway inhibition. Reason: Downstream pleiotropic effect. Supporting Evidence: PMID:19208814 Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.
GO:0060024 rhythmic synaptic transmission	ISS PMID:17706614 A seizure-prone phenotype is associated with altered free-ru...	MARK AS OVER ANNOTATED	Summary: PTEN affects rhythmic synaptic transmission in circadian circuits. Reason: Very specialized neuronal function. Supporting Evidence: PMID:17706614 2007 Jul 20. A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice.
GO:0060074 synapse maturation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN regulates synapse maturation through PI3K/mTOR signaling. Reason: Neuronal-specific developmental effect.
GO:0060134 prepulse inhibition	ISS PMID:19208814 Haploinsufficiency for Pten and Serotonin transporter cooper...	MARK AS OVER ANNOTATED	Summary: PTEN affects sensorimotor gating (prepulse inhibition). Reason: Very specialized behavioral/neurological phenotype. Supporting Evidence: PMID:19208814 Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.
GO:0060997 dendritic spine morphogenesis	ISS PMID:18082964 Phosphatase and tensin homolog, deleted on chromosome 10 def...	KEEP AS NON CORE	Summary: PTEN regulates dendritic spine morphology through PI3K/mTOR signaling. Reason: Neuronal-specific structural effect. Supporting Evidence: PMID:18082964 Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
GO:0090394 negative regulation of excitatory postsynaptic potential	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects synaptic transmission. Reason: Neuronal-specific effect.
GO:0097105 presynaptic membrane assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects presynaptic structure. Reason: Neuronal-specific structural effect.
GO:0097107 postsynaptic density assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects postsynaptic structure via PI3K/mTOR signaling. Reason: Neuronal-specific structural effect.
GO:1990757 ubiquitin ligase activator activity	ISS PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	ACCEPT	Summary: Nuclear PTEN activates APC-CDH1 E3 ubiquitin ligase in a phosphatase-independent manner. Reason: This represents a non-canonical function of nuclear PTEN that is independent of its phosphatase activity but important for tumor suppression. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner
GO:2000463 positive regulation of excitatory postsynaptic potential	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects synaptic transmission. Reason: Neuronal-specific effect. Note this conflicts with GO:0090394 (negative regulation) which may indicate context-dependency.
GO:2000808 negative regulation of synaptic vesicle clustering	ISS PMID:18082964 Phosphatase and tensin homolog, deleted on chromosome 10 def...	KEEP AS NON CORE	Summary: PTEN affects synaptic vesicle organization. Reason: Neuronal-specific structural effect. Supporting Evidence: PMID:18082964 Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
GO:0007056 spindle assembly involved in female meiosis	IDA PMID:31492966 The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic ...	KEEP AS NON CORE	Summary: PTEN degradation is required for oocyte meiotic resumption. PTEN affects spindle assembly during oocyte meiosis. Reason: Specialized cell type-specific role in meiosis. Not a core molecular function. Supporting Evidence: PMID:31492966 Epub 2019 Sep 6. The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IDA PMID:31492966 The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic ...	ACCEPT	Summary: Core process annotation. PTEN negatively regulates PI3K/AKT signaling in oocytes. Reason: Duplicate of TAS/ISS annotations. Core function. Supporting Evidence: PMID:31492966 Epub 2019 Sep 6. The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation.
GO:0052866 phosphatidylinositol phosphate phosphatase activity	IDA PMID:9811831 The lipid phosphatase activity of PTEN is critical for its t...	ACCEPT	Summary: General phosphatidylinositol phosphate phosphatase activity. The more specific GO:0016314 (PIP3 3-phosphatase) is preferred. Reason: Accurate parent term for PTEN's lipid phosphatase activities. Supporting Evidence: PMID:9811831 Characterization of the lipid phosphatase activity of PTEN demonstrates that it shows specificity for phosphatidylinositols phosphorylated at the 3 position
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5689950	ACCEPT	Summary: Duplicate nucleoplasm annotation. PTEN localizes to nucleoplasm. Reason: Nuclear PTEN localization is well-established.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6807118	ACCEPT	Summary: Duplicate nucleoplasm annotation. Reason: Consistent with other nucleoplasm annotations.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6807126	ACCEPT	Summary: Duplicate nucleoplasm annotation. Reason: Consistent with other nucleoplasm annotations.
GO:2000773 negative regulation of cellular senescence	ISS PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	KEEP AS NON CORE	Summary: Nuclear PTEN affects cellular senescence through APC-CDH1 complex regulation. Reason: Downstream effect of PTEN's nuclear functions. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:0033137 negative regulation of peptidyl-serine phosphorylation	IMP PMID:10918569 PTEN expression is reduced in a subset of sporadic thyroid c...	KEEP AS NON CORE	Summary: PTEN inhibits AKT-mediated serine phosphorylation of downstream targets by reducing PIP3 levels. Reason: This is an indirect consequence of PTEN's inhibition of AKT signaling. Supporting Evidence: PMID:10918569 PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1.
GO:1902807 negative regulation of cell cycle G1/S phase transition	IDA PMID:10918569 PTEN expression is reduced in a subset of sporadic thyroid c...	KEEP AS NON CORE	Summary: PTEN inhibits G1/S transition through AKT-mediated effects on cell cycle regulators like p27. Reason: Downstream effect of PI3K/AKT pathway inhibition. Supporting Evidence: PMID:10918569 PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1.
GO:0005829 cytosol	TAS Reactome:R-HSA-2317387	ACCEPT	Summary: Duplicate cytosol annotation. Reason: Consistent with IBA and IDA cytosol annotations.
GO:0010977 negative regulation of neuron projection development	ISS PMID:28008308 The Protective Role of microRNA-200c in Alzheimer's Disease ...	KEEP AS NON CORE	Summary: PTEN negatively regulates neuron projection development through PI3K/mTOR signaling. Reason: Neuronal-specific downstream effect. Supporting Evidence: PMID:28008308 eCollection 2016. The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.
GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation	IMP PMID:26208095 PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Hum...	KEEP AS NON CORE	Summary: PTEN suppresses vascular smooth muscle cell proliferation through PI3K/AKT pathway inhibition. Reason: Cell type-specific downstream effect of PTEN's core lipid phosphatase function. Supporting Evidence: PMID:26208095 eCollection 2015. PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21.
GO:0005515 protein binding	IPI PMID:15355975 Regulation of PTEN phosphorylation and stability by a tumor ...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with NOP53 which regulates PTEN stability. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:15355975 2004 Sep 7. Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein.
GO:0005515 protein binding	IPI PMID:25007873 TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with PPP1R16B (TIMAP) in endothelial cells. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:25007873 TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	NAS PMID:16762633 Involvement of human micro-RNA in growth and response to che...	ACCEPT	Summary: Core process annotation. Duplicate of IDA/TAS/ISS annotations. Reason: Core biological process for PTEN. Supporting Evidence: PMID:16762633 Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:22879939 TGFβ-stimulated microRNA-21 utilizes PTEN to orchestrate AKT...	ACCEPT	Summary: Core process annotation. Duplicate. Reason: Core biological process for PTEN. Supporting Evidence: PMID:22879939 TGFβ-stimulated microRNA-21 utilizes PTEN to orchestrate AKT/mTORC1 signaling for mesangial cell hypertrophy and matrix expansion.
GO:0010719 negative regulation of epithelial to mesenchymal transition	IMP PMID:27919618 Electric field-induced suppression of PTEN drives epithelial...	KEEP AS NON CORE	Summary: PTEN suppresses EMT through PI3K/AKT pathway inhibition. Reason: Downstream process related to PTEN's tumor suppressor function. Supporting Evidence: PMID:27919618 Epub 2016 Nov 18. Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.
GO:0051548 negative regulation of keratinocyte migration	IMP PMID:27919618 Electric field-induced suppression of PTEN drives epithelial...	KEEP AS NON CORE	Summary: PTEN inhibits keratinocyte migration through PI3K/AKT signaling. Reason: Cell type-specific migration effect. Supporting Evidence: PMID:27919618 Epub 2016 Nov 18. Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.
GO:0071257 cellular response to electrical stimulus	IMP PMID:27919618 Electric field-induced suppression of PTEN drives epithelial...	MARK AS OVER ANNOTATED	Summary: PTEN affects cellular responses to electrical stimulation in wound healing contexts. Reason: Very specialized experimental context. Distant from core function. Supporting Evidence: PMID:27919618 Epub 2016 Nov 18. Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.
GO:1903690 negative regulation of wound healing, spreading of epidermal cells	IMP PMID:27919618 Electric field-induced suppression of PTEN drives epithelial...	KEEP AS NON CORE	Summary: PTEN inhibits epidermal cell spreading during wound healing. Reason: Tissue-specific effect related to PTEN's effects on cell motility. Supporting Evidence: PMID:27919618 Epub 2016 Nov 18. Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses...	ACCEPT	Summary: Core process annotation. Duplicate. Reason: Core biological process for PTEN. Supporting Evidence: PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.
GO:1990381 ubiquitin-specific protease binding	IPI PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses...	ACCEPT	Summary: PTEN binds USP13 which deubiquitinates and stabilizes PTEN. Reason: This is a specific binding activity relevant to PTEN regulation. More informative than generic protein binding. Supporting Evidence: PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.
GO:0005829 cytosol	TAS Reactome:R-HSA-1676149	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Cytosolic localization is well-established for PTEN.
GO:0005829 cytosol	TAS Reactome:R-HSA-1855205	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-199456	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-2321904	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-6807106	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-6807126	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-6807134	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-6807206	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8847968	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8847977	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8850945	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8850961	ACCEPT	Summary: Duplicate cytosol annotation from Reactome. Reason: Consistent with other cytosol annotations.
GO:0030336 negative regulation of cell migration	IMP PMID:21573166 Upregulated microRNA-29a by hepatitis B virus X protein enha...	KEEP AS NON CORE	Summary: PTEN inhibits cell migration through PI3K/AKT pathway inhibition. Reason: Downstream effect of PTEN's lipid phosphatase activity. Well-documented but not a core molecular function. Supporting Evidence: PMID:9616126 Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN PMID:21573166 Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:21573166 Upregulated microRNA-29a by hepatitis B virus X protein enha...	ACCEPT	Summary: Core process annotation. Duplicate. Reason: Core biological process for PTEN. Supporting Evidence: PMID:21573166 Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6807105	ACCEPT	Summary: Duplicate nucleoplasm annotation. Reason: Consistent with other nucleoplasm annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-6807105	ACCEPT	Summary: Duplicate cytosol annotation. Reason: Consistent with other cytosol annotations.
GO:0005634 nucleus	IDA PMID:24862762 NHERF1/EBP50 controls morphogenesis of 3D colonic glands by ...	ACCEPT	Summary: PTEN nuclear localization is important for its protein phosphatase functions and genomic stability Reason: Nuclear localization enables PTEN's protein phosphatase activity and non-canonical tumor suppressor functions Supporting Evidence: PMID:24862762 NHERF1/EBP50 controls morphogenesis of 3D colonic glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane.
GO:0005737 cytoplasm	IDA PMID:24862762 NHERF1/EBP50 controls morphogenesis of 3D colonic glands by ...	ACCEPT	Summary: Duplicate cytoplasm annotation. Reason: Cytoplasmic localization is well-established for PTEN. Supporting Evidence: PMID:24862762 NHERF1/EBP50 controls morphogenesis of 3D colonic glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane.
GO:0008284 positive regulation of cell population proliferation	ISS GO_REF:0000024	UNDECIDED	Summary: PTEN generally negatively regulates cell proliferation. Positive regulation may be context-specific. Reason: This contradicts PTEN's well-established role as an inhibitor of cell proliferation. May be context-specific or incorrectly assigned.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	TAS PMID:18082964 Phosphatase and tensin homolog, deleted on chromosome 10 def...	ACCEPT	Summary: Core process annotation. Duplicate. Reason: Core biological process for PTEN. Supporting Evidence: PMID:18082964 Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
GO:0007416 synapse assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN regulates synapse assembly through PI3K/mTOR signaling. Reason: Neuronal-specific developmental effect.
GO:0033555 multicellular organismal response to stress	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Very broad term with unclear mechanistic basis. Reason: Too vague to be informative.
GO:0048853 forebrain morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects forebrain development through PI3K/mTOR signaling regulation of cell growth. Reason: Tissue-specific developmental effect.
GO:0050771 negative regulation of axonogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN inhibits axon growth through PI3K/mTOR pathway. Reason: Neuronal-specific effect.
GO:0005515 protein binding	IPI PMID:19473982 X-linked inhibitor of apoptosis protein (XIAP) regulates PTE...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with XIAP which ubiquitinates PTEN. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:19473982 2009 May 27. X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization.
GO:0046856 phosphatidylinositol dephosphorylation	IMP PMID:21828076 A comprehensive functional analysis of PTEN mutations: impli...	ACCEPT	Summary: Core process annotation. PTEN dephosphorylates phosphatidylinositols. Reason: Core biological process for PTEN. Supporting Evidence: PMID:21828076 Aug 9. A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.
GO:0008285 negative regulation of cell population proliferation	IMP PMID:17880912 MAGI-2 Inhibits cell migration and proliferation via PTEN in...	KEEP AS NON CORE	Summary: PTEN suppresses cell proliferation through PI3K/AKT pathway inhibition. Reason: Downstream effect of PTEN's core lipid phosphatase activity. Supporting Evidence: PMID:17880912 Epub 2007 Aug 22. MAGI-2 Inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells.
GO:0030336 negative regulation of cell migration	IMP PMID:17880912 MAGI-2 Inhibits cell migration and proliferation via PTEN in...	KEEP AS NON CORE	Summary: PTEN inhibits cell migration. Duplicate annotation. Reason: Downstream effect of PTEN's lipid phosphatase activity. Supporting Evidence: PMID:17880912 Epub 2007 Aug 22. MAGI-2 Inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells.
GO:0005737 cytoplasm	IDA PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a me...	ACCEPT	Summary: Duplicate cytoplasm annotation. Reason: Consistent with other cytoplasm annotations. Supporting Evidence: PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.
GO:0004721 phosphoprotein phosphatase activity	IDA PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	ACCEPT	Summary: PTEN has phosphoprotein phosphatase activity in the nucleus. Reason: This protein phosphatase activity has been demonstrated experimentally. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:0005634 nucleus	IDA PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	ACCEPT	Summary: Nuclear PTEN localization for APC-CDH1 regulation. Reason: Well-documented nuclear localization with specific function. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:0005737 cytoplasm	IDA PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	ACCEPT	Summary: Duplicate cytoplasm annotation. Reason: Consistent with other cytoplasm annotations. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:0010997 anaphase-promoting complex binding	IPI PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	ACCEPT	Summary: Nuclear PTEN binds the APC-CDH1 complex to activate its E3 ligase activity. Reason: This represents an important phosphatase-independent function of nuclear PTEN. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner
GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process	IDA PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	KEEP AS NON CORE	Summary: Nuclear PTEN activates APC-CDH1 to promote ubiquitin-dependent degradation of its substrates. Reason: This is a downstream effect of PTEN's interaction with APC-CDH1, not a core function. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:2000134 negative regulation of G1/S transition of mitotic cell cycle	IDA PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple...	KEEP AS NON CORE	Summary: Nuclear PTEN suppresses G1/S transition through APC-CDH1 activation. Reason: Downstream effect of PTEN's nuclear APC-CDH1 activating function. Supporting Evidence: PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
GO:0005515 protein binding	IPI PMID:17242191 NHERF1/EBP50 head-to-tail intramolecular interaction masks a...	MARK AS OVER ANNOTATED	Summary: PTEN interacts with DJ-1 which affects PTEN function. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:17242191 Jan 22. NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands.
GO:0008285 negative regulation of cell population proliferation	IDA PMID:19057511 PTEN regulation by Akt-EGR1-ARF-PTEN axis.	KEEP AS NON CORE	Summary: PTEN suppresses cell proliferation. Duplicate annotation. Reason: Downstream effect of PTEN's lipid phosphatase activity. Supporting Evidence: PMID:19057511 PTEN regulation by Akt-EGR1-ARF-PTEN axis.
GO:0005737 cytoplasm	IDA PMID:10940933 Subcellular localization of intracellular protein tyrosine p...	ACCEPT	Summary: Duplicate cytoplasm annotation. Reason: Consistent with other cytoplasm annotations. Supporting Evidence: PMID:10940933 Subcellular localization of intracellular protein tyrosine phosphatases in T cells.
GO:0050821 protein stabilization	IDA PMID:20123964 Lipid phosphate phosphatase 3 stabilization of beta-catenin ...	UNDECIDED	Summary: This annotation appears to be from a study on LPP3, not PTEN. Reason: Need to verify reference relevance. PMID:20123964 is about LPP3. Supporting Evidence: PMID:20123964 Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
GO:0019899 enzyme binding	IPI PMID:16845383 Critical role for Daxx in regulating Mdm2.	ACCEPT	Summary: PTEN interacts with NDR kinases. Reason: More informative than generic protein binding. Supporting Evidence: PMID:16845383 Critical role for Daxx in regulating Mdm2.
GO:0010975 regulation of neuron projection development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN regulates neuron projection development through PI3K/mTOR signaling. Reason: Neuronal-specific effect.
GO:0005634 nucleus	IDA PMID:17218261 Ubiquitination regulates PTEN nuclear import and tumor suppr...	ACCEPT	Summary: Nuclear localization of PTEN regulated by ubiquitination. Reason: Consistent with other nuclear PTEN annotations. Supporting Evidence: PMID:17218261 Ubiquitination regulates PTEN nuclear import and tumor suppression
GO:0051800 phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity	IDA PMID:9811831 The lipid phosphatase activity of PTEN is critical for its t...	ACCEPT	Summary: PTEN can dephosphorylate PI(3,4)P2 at the D3 position. Reason: Documented enzymatic activity. Supporting Evidence: PMID:9811831 Characterization of the lipid phosphatase activity of PTEN demonstrates that it shows specificity for phosphatidylinositols phosphorylated at the 3 position
GO:0051895 negative regulation of focal adhesion assembly	IMP PMID:9616126 Inhibition of cell migration, spreading, and focal adhesions...	KEEP AS NON CORE	Summary: PTEN inhibits focal adhesion formation through PI3K/AKT pathway modulation. Reason: Downstream effect related to PTEN's effects on cell motility. Supporting Evidence: PMID:9616126 Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a me...	ACCEPT	Summary: Core process annotation. PTEN suppresses AKT activation. Reason: Core biological process for PTEN. Supporting Evidence: PMID:10760291 MAGI-2 enhances the ability of PTEN to suppress Akt activation
GO:0004438 phosphatidylinositol-3-phosphate phosphatase activity	IDA PMID:9811831 The lipid phosphatase activity of PTEN is critical for its t...	ACCEPT	Summary: PTEN can dephosphorylate PI(3)P. Secondary substrate. Reason: Documented activity, though PIP3 is the primary substrate. Supporting Evidence: PMID:9811831 The lipid phosphatase activity of PTEN is critical for its tumor supressor function.
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:9256433 P-TEN, the tumor suppressor from human chromosome 10q23, is ...	ACCEPT	Summary: PTEN has dual-specificity protein phosphatase activity including serine/threonine. Reason: Core molecular function documented in the seminal paper. Supporting Evidence: PMID:9256433 recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues, indicating that P-TEN is a dual-specificity phosphatase
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:9256433 P-TEN, the tumor suppressor from human chromosome 10q23, is ...	ACCEPT	Summary: PTEN has protein tyrosine phosphatase activity. Reason: Core molecular function documented experimentally. Supporting Evidence: PMID:9256433 recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues
GO:0005737 cytoplasm	IDA PMID:9187108 TEP1, encoded by a candidate tumor suppressor locus, is a no...	ACCEPT	Summary: Early documentation of PTEN cytoplasmic localization. Reason: Consistent with other cytoplasm annotations. Supporting Evidence: PMID:9187108 TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.
GO:0006470 protein dephosphorylation	IDA PMID:9256433 P-TEN, the tumor suppressor from human chromosome 10q23, is ...	ACCEPT	Summary: PTEN has protein phosphatase activity. Core process for its dual-specificity phosphatase function. Reason: Documented experimentally in the seminal paper. Supporting Evidence: PMID:9256433 recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues
GO:0008285 negative regulation of cell population proliferation	IMP PMID:10468583 The tumor-suppressor activity of PTEN is regulated by its ca...	KEEP AS NON CORE	Summary: PTEN suppresses cell proliferation. Duplicate annotation. Reason: Downstream effect of PTEN's lipid phosphatase activity. Supporting Evidence: PMID:10468583 The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region.
GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity	IDA PMID:9811831 The lipid phosphatase activity of PTEN is critical for its t...	ACCEPT	Summary: Core molecular function of PTEN. This is the primary enzymatic activity. Reason: Essential for tumor suppression. Core molecular function. Supporting Evidence: PMID:9811831 Here we report that a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease
GO:0030165 PDZ domain binding	IPI PMID:10646847 Threonine phosphorylation of the MMAC1/PTEN PDZ binding doma...	ACCEPT	Summary: PTEN binds PDZ domains through its C-terminal motif. Important for localization and stability. Reason: Well-documented interaction important for PTEN regulation. Supporting Evidence: PMID:10646847 Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and stimulates PDZ binding.
GO:0030165 PDZ domain binding	IPI PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a me...	ACCEPT	Summary: PTEN binds MAGI-2 PDZ domain. Important for membrane localization and function. Reason: Core binding activity for PTEN localization and function. Supporting Evidence: PMID:10760291 PTEN binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2
GO:0030336 negative regulation of cell migration	IMP PMID:9616126 Inhibition of cell migration, spreading, and focal adhesions...	KEEP AS NON CORE	Summary: PTEN inhibits cell migration through PI3K/AKT pathway inhibition. Reason: Downstream effect of PTEN's lipid phosphatase activity. Supporting Evidence: PMID:9616126 Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN
GO:0046856 phosphatidylinositol dephosphorylation	IDA PMID:9811831 The lipid phosphatase activity of PTEN is critical for its t...	ACCEPT	Summary: Core biological process for PTEN. Reason: Primary process in which PTEN participates. Supporting Evidence: PMID:9811831 The lipid phosphatase activity of PTEN is critical for its tumor supressor function.
GO:0051717 inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity	IDA PMID:9593664 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid...	ACCEPT	Summary: PTEN can dephosphorylate soluble inositol polyphosphates. Reason: Documented enzymatic activity. Supporting Evidence: PMID:9593664 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.
GO:0005737 cytoplasm	TAS PMID:9367992 A family of putative tumor suppressors is structurally and f...	ACCEPT	Summary: Duplicate cytoplasm annotation. Reason: Consistent with other cytoplasm annotations. Supporting Evidence: PMID:9367992 A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast.
GO:0006470 protein dephosphorylation	TAS PMID:9367992 A family of putative tumor suppressors is structurally and f...	ACCEPT	Summary: PTEN has protein dephosphorylation activity. Reason: Part of PTEN's dual-specificity phosphatase function. Supporting Evidence: PMID:9367992 A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast.
GO:0007417 central nervous system development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects CNS development through PI3K/mTOR signaling. Reason: Tissue-specific developmental effect.
GO:0007507 heart development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN affects heart development through PI3K/AKT signaling. Reason: Tissue-specific developmental effect.
GO:0016477 cell migration	ISS GO_REF:0000024	MODIFY	Summary: PTEN regulates cell migration. More specific negative regulation terms exist. Reason: GO:0030336 (negative regulation of cell migration) is more accurate for PTEN's inhibitory effect. Proposed replacements: negative regulation of cell migration
GO:0031647 regulation of protein stability	IMP PMID:10866658 Phosphorylation of the PTEN tail regulates protein stability...	KEEP AS NON CORE	Summary: PTEN affects protein stability, possibly through AKT-mediated effects. Reason: Indirect effect through signaling pathway modulation. Supporting Evidence: PMID:10866658 Phosphorylation of the PTEN tail regulates protein stability and function.
GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity	IDA PMID:9593664 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid...	ACCEPT	Summary: Core molecular function. Duplicate annotation. Reason: Primary enzymatic activity of PTEN. Supporting Evidence: PMID:9593664 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.
GO:0014069 postsynaptic density	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: PTEN localizes to postsynaptic densities in neurons. Reason: Neuronal-specific localization.
GO:0016605 PML body	IEA GO_REF:0000044	ACCEPT	Summary: PTEN can localize to PML nuclear bodies. Reason: Relevant for PTEN's nuclear functions and regulation by ubiquitination.
GO:0042995 cell projection	IEA GO_REF:0000117	ACCEPT	Summary: Duplicate of IBA annotation. PTEN localizes to cell projections. Reason: Consistent with IBA annotation.
GO:0043197 dendritic spine	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: PTEN localizes to dendritic spines in neurons. Reason: Neuronal-specific localization.
GO:0097225 sperm midpiece	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: PTEN localizes to sperm midpiece. Reason: Cell type-specific localization.
GO:0097228 sperm principal piece	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: PTEN localizes to sperm principal piece. Reason: Cell type-specific localization.
GO:0140678 molecular function inhibitor activity	IMP PMID:23744781 A secreted PTEN phosphatase that enters cells to alter signa...	ACCEPT	Summary: PTEN-L isoform can be secreted and inhibit PI3K signaling in recipient cells. Reason: This describes the paracrine tumor suppressor activity of secreted PTEN-L. Supporting Evidence: PMID:23744781 A secreted PTEN phosphatase that enters cells to alter signaling and survival
GO:0005829 cytosol	TAS Reactome:R-HSA-8850992	ACCEPT	Summary: Duplicate cytosol annotation. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8850997	ACCEPT	Summary: Duplicate cytosol annotation. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8851011	ACCEPT	Summary: Duplicate cytosol annotation. Reason: Consistent with other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8873946	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Consistent with other cytosol annotations. PTEN is a cytosolic protein that translocates to the plasma membrane for its lipid phosphatase function.
GO:0005829 cytosol	TAS Reactome:R-HSA-8944497	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Consistent with other cytosol annotations. PTEN is a cytosolic protein that translocates to the plasma membrane for its lipid phosphatase function.
GO:0005829 cytosol	TAS Reactome:R-HSA-8948775	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Consistent with other cytosol annotations. PTEN is a cytosolic protein that translocates to the plasma membrane for its lipid phosphatase function.
GO:0005829 cytosol	TAS Reactome:R-HSA-8948800	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Consistent with other cytosol annotations. PTEN is a cytosolic protein that translocates to the plasma membrane for its lipid phosphatase function.
GO:0005829 cytosol	TAS Reactome:R-HSA-8948832	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Consistent with other cytosol annotations. PTEN is a cytosolic protein that translocates to the plasma membrane for its lipid phosphatase function.
GO:0005829 cytosol	TAS Reactome:R-HSA-9615571	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Consistent with other cytosol annotations. PTEN is a cytosolic protein that translocates to the plasma membrane for its lipid phosphatase function.
GO:0016324 apical plasma membrane	IMP PMID:24862762 NHERF1/EBP50 controls morphogenesis of 3D colonic glands by ...	ACCEPT	Summary: PTEN localizes to the apical plasma membrane in polarized epithelial cells, stabilized by NHERF1/EBP50 interaction. Reason: The publication demonstrates that PTEN localizes apically in polarized epithelial cells through its C-terminal PDZ-binding motif interaction with NHERF1. This apical localization is important for maintaining PIP2/PIP3 distribution and epithelial polarity. Supporting Evidence: PMID:24862762 NHERF1 stabilizes PTEN apically through PDZ-domain interactions [5] , and NHERF1 loss leads to PTEN cytosolic redistribution
GO:0042995 cell projection	IDA PMID:25007873 TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt...	UNDECIDED	Summary: PTEN localization to cell projections in endothelial cells based on TIMAP colocalization studies. Reason: The publication PMID:25007873 focuses on TIMAP regulation of PTEN activity and shows colocalization, but the full text is not available to confirm specific cell projection localization data. The abstract does not directly address cell projection localization. Supporting Evidence: PMID:25007873 TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells.
GO:0035749 myelin sheath adaxonal region	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN localization to myelin sheath adaxonal region inferred from sequence similarity. Reason: This is a highly specialized cell type-specific localization in myelinating Schwann cells. While PTEN plays important roles in myelination, this represents a cell type-specific localization rather than a core function annotation.
GO:0043220 Schmidt-Lanterman incisure	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PTEN localization to Schmidt-Lanterman incisures in myelin sheath inferred from sequence similarity. Reason: This is a highly specialized localization in peripheral nerve myelin sheaths. While PTEN is important for Schwann cell function and myelination, this represents a cell type-specific localization rather than a core function annotation.
GO:0042995 cell projection	IDA PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a me...	UNDECIDED	Summary: This annotation is likely incorrect for PMID:10760291, which focuses on MAGI-2 PDZ domain interactions. Reason: PMID:10760291 describes PTEN binding to MAGI-2 at tight junctions in epithelial cell membranes, not specifically cell projections. The cell projection annotation may be a misinterpretation of the membrane localization data. The reference discusses membrane localization through MAGI-2 scaffold interactions but does not specifically characterize cell projection localization. Supporting Evidence: PMID:10760291 Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.
GO:0009898 cytoplasmic side of plasma membrane	IDA PMID:10940933 Subcellular localization of intracellular protein tyrosine p...	ACCEPT	Summary: PTEN localizes to the cytoplasmic side of the plasma membrane in T cells. Reason: The publication directly examines subcellular localization of intracellular protein tyrosine phosphatases including PTEN in T cells. PTEN was found enriched at the plasma membrane, consistent with its function in dephosphorylating membrane-associated PIP3. This localization is essential for its core lipid phosphatase function. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.

Core Functions

dephosphorylating PIP3 to PIP2 at the plasma membrane to antagonize PI3K/AKT signaling

Molecular Function:

phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity

Directly Involved In:

negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction phosphatidylinositol dephosphorylation

Cellular Locations:

plasma membrane cytosol

Supporting Evidence:

PMID:10760291
PTEN acts as a PIP3 3-phosphatase, converting PIP3 to PIP2 and thereby antagonizing PI3K signaling
PMID:9811831
PTEN phosphatase activity is essential for its tumor suppressor function by negatively regulating the PI3K/AKT pathway

dephosphorylating PIP2 to PIP at the plasma membrane

Molecular Function:

phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity

Directly Involved In:

phosphatidylinositol dephosphorylation

Cellular Locations:

plasma membrane cytosol

Supporting Evidence:

PMID:10760291
PTEN also exhibits PIP2 3-phosphatase activity in addition to its primary PIP3 phosphatase function

dephosphorylating protein substrates at serine and threonine residues

Molecular Function:

protein serine/threonine phosphatase activity

Directly Involved In:

protein dephosphorylation

Cellular Locations:

nucleus cytosol

Supporting Evidence:

PMID:21241890
PTEN possesses protein phosphatase activity toward serine and threonine residues on protein substrates
PMID:9256433
PTEN exhibits dual phosphatase activity against both lipid and protein substrates

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms.

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

PMID:10468583

The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region.

PMID:10646847

Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and stimulates PDZ binding.

PMID:10760291

Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.

PMID:10866658

Phosphorylation of the PTEN tail regulates protein stability and function.

PMID:10918569

PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1.

PMID:10940933

Subcellular localization of intracellular protein tyrosine phosphatases in T cells.

PMID:11418101

Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity.

PMID:15355975

Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein.

PMID:15951562

Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases.

PMID:16456542

PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling.

PMID:16675393

Pten regulates neuronal arborization and social interaction in mice.

PMID:16762633

Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.

PMID:16845383

Critical role for Daxx in regulating Mdm2.

PMID:17218261

Ubiquitination regulates PTEN nuclear import and tumor suppression.

PMID:17242191

NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands.

PMID:17274640

A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis.

PMID:17706614

A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice.

PMID:17880912

MAGI-2 Inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells.

PMID:18082964

Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.

PMID:19057511

PTEN regulation by Akt-EGR1-ARF-PTEN axis.

PMID:19208814

Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.

PMID:19345329

Rak functions as a tumor suppressor by regulating PTEN protein stability and function.

PMID:19369943

Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity.

PMID:19473982

X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization.

PMID:19903340

PTEN inhibits BMI1 function independently of its phosphatase activity.

PMID:20123964

Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.

PMID:21241890

Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.

PMID:21411674

Pten knockdown in vivo increases excitatory drive onto dentate granule cells.

PMID:21573166

Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model.

PMID:21653829

Protein interactome reveals converging molecular pathways among autism disorders.

PMID:21804599

PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma.

PMID:21828076

A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.

PMID:22869525

Insulin-like growth factor (IGF) binding protein 2 functions coordinately with receptor protein tyrosine phosphatase β and the IGF-I receptor to regulate IGF-I-stimulated signaling.

PMID:22879939

TGFβ-stimulated microRNA-21 utilizes PTEN to orchestrate AKT/mTORC1 signaling for mesangial cell hypertrophy and matrix expansion.

PMID:23514585

PTEN suppresses the oncogenic function of AIB1 through decreasing its protein stability via mechanism involving Fbw7 alpha.

PMID:23940795

Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN.

PMID:24012959

Breast cancer-derived K172N, D301V mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of platelet-derived growth factor receptor signaling.

PMID:24656772

SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer.

PMID:24766807

Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function.

PMID:24862762

NHERF1/EBP50 controls morphogenesis of 3D colonic glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane.

PMID:25007873

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells.

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:26208095

PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21.

PMID:26280536

Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.

PMID:27919618

Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.

PMID:28008308

The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.

PMID:31492966

The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation.

PMID:36950384

Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders.

PMID:9187108

TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.

PMID:9256433

P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.

PMID:9367992

A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast.

PMID:9593664

The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.

PMID:9616126

Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.

PMID:9811831

The lipid phosphatase activity of PTEN is critical for its tumor supressor function.

Reactome:R-HSA-1660499

Synthesis of PIPs at the plasma membrane

Reactome:R-HSA-1676149

PI(3,4)P2 is dephosphorylated to PI4P by PTEN at the plasma membrane

Reactome:R-HSA-1855205

I(1,3,4,5)P4 is dephosphorylated to I(1,4,5)P3 by PTEN in the cytosol

Reactome:R-HSA-199456

PTEN dephosphorylates PIP3

Reactome:R-HSA-2317387

PTEN cancer mutants do not dephosphorylate PIP3

Reactome:R-HSA-2321904

PTEN mRNA translation negatively regulated by microRNAs

Reactome:R-HSA-5689950

USP7 deubiquitinates TP53,MDM2,MDM4,FOXO4, PTEN

Reactome:R-HSA-6807105

Monoubiquitinated PTEN translocates to the nucleus

Reactome:R-HSA-6807106

PTEN undergoes monoubiquitination

Reactome:R-HSA-6807118

USP7 deubiquitinates monoubiquitinated PTEN

Reactome:R-HSA-6807126

Deubiquitinated PTEN translocates to the cytosol

Reactome:R-HSA-6807134

NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN

Reactome:R-HSA-6807206

USP13 and OTUD3 deubiquitinate PTEN

Reactome:R-HSA-8847968

PTEN binds FRK

Reactome:R-HSA-8847977

FRK phosphorylates PTEN

Reactome:R-HSA-8850945

Casein kinase II phosphorylates PTEN

Reactome:R-HSA-8850961

PREX2 binds PTEN and inhibits it

PMID:23744781

A secreted PTEN phosphatase that enters cells to alter signaling and survival.

Reactome:R-HSA-8850992

Proteasome degrades polyubiquitinated PTEN

Reactome:R-HSA-8850997

TRIM27 binds PTEN

Reactome:R-HSA-8851011

TRIM27 polyubiquitinates PTEN

Reactome:R-HSA-8873946

OTUD3 deubiquitinates PTEN

Reactome:R-HSA-8944497

PTEN mRNA translation is negatively regulated by microRNAs

Reactome:R-HSA-8948775

MKRN1 polyubiquitinates PTEN

Reactome:R-HSA-8948800

TNKS and TNKS2 PARylate PTEN

Reactome:R-HSA-8948832

RNF146 polyubiquitinates PARylated PTEN

Reactome:R-HSA-9615571

PTEN mRNA translation is inhibited by miR-137

file:human/PTEN/PTEN-deep-research-falcon.md

Deep research on PTEN function

📚 Additional Documentation

Deep Research Bioreason

(PTEN-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 03:09 AM

Organism: Homo sapiens

Sequence:

MTAIIKEIVSRNKRRYQEDGFDLDLTYIYPNIIAMGFPAERLEGVYRNNIDDVVRFLDSKHKNHYKIYNLCAERHYDTAKFNCRVAQYPFEDHNPPQLELIKPFCEDLDQWLSEDDNHVAAIHCKAGKGRTGVMICAYLLHRGKFLKAQEALDFYGEVRTRDKKGVTIPSQRRYVYYYSYLLKNHLDYRPVALLFHKMMFETIPMFSGGTCNPQFVVCQLKVKIYSSNSGPTRREDKFMYFEFPQPLPVCGDIKVEFFHKQNKMLKKDKMFHFWVNTFFIPGPEETSEKVENGSLCDQEIDSICSIERADNDKEYLVLTLTKNDLDKANKDKANRYFSPNFKVKLYFTKTVEEPSNPEASSSTSVTPDVSDNEPDHYRYSDTTDSDPENEPFDEDQHTQITKV

Thinking Trace

I begin with the InterPro architecture. The N-terminal half (residues 1–403) is saturated with phosphatase signatures: IPR029021 (Protein-tyrosine phosphatase-like homologous superfamily, residues 1–187) frames the fold; IPR003595 (Protein-tyrosine phosphatase, catalytic domain, residues 23–183) and IPR045101 (PTEN phosphatase domain, residues 24–181) define the catalytic core; IPR000387 (Tyrosine-specific protein phosphatases domain, residues 102–173) and IPR016130 (Protein-tyrosine phosphatase active site, residues 122–132) pinpoint the essential cysteine-based nucleophile and arginine-stabilizing cage that drive hydrolysis of phosphate monoesters. This N-terminal catalytic engine is reinforced by PTEN/tyrosine phosphatase family assignments IPR017361 (Bifunctional phosphatidylinositol trisphosphate phosphatase/dual specificity phosphatase PTEN family, residues 1–403) and IPR051281 (Dual-specificity lipid and protein phosphatase family, residues 1–377), which specify that the same active site accommodates both lipid and protein substrates. Immediately downstream, the C-terminal half is dominated by membrane-targeting modules: IPR029023 (Tensin-type phosphatase domain, residues 14–185) transitions into a membrane-binding region annotated as IPR035892 (C2 domain superfamily, residues 188–349) and IPR014020 (Tensin phosphatase, C2 domain, residues 188–350). This arrangement—an N-terminal cysteine-dependent PTP fold followed by a C2 membrane-targeting module—creates a bifunctional enzyme: the catalytic head performs phosphate removal, while the C2 domain docks the enzyme onto acidic membranes to access membrane-embedded lipid substrates.

This domain architecture causes two coupled molecular functions. First, the conserved PTP fold and active-site signature (IPR016130) establish phosphatase chemistry that removes phosphate groups from tyrosine and, by extension, from certain protein residues; this supports GO:0004725 protein tyrosine phosphatase activity and explains dual-specificity behavior. Second, the PTEN family and tensin-type arrangement (IPR017361, IPR051281) together with membrane-anchoring C2 modules direct the same catalytic apparatus toward phosphoinositide headgroups, supporting phosphatidylinositol phosphate phosphatase activity that converts PI(3,4,5)P3 to PI(4,5)P2 at membrane surfaces. The convergence of these motifs functionally manifests as a lipid/protein phosphatase capable of sculpting signaling lipids.

From these molecular activities, the biological process follows. By depleting PI(3,4,5)P3 at the cytoplasmic face of membranes, the enzyme attenuates phosphoinositide-dependent pathways that govern cell survival and proliferation. This directly tunes insulin and growth factor signaling and biases fate decisions toward controlled growth rather than unregulated proliferation. Consequently, the architecture-driven phosphatase activity situates the protein squarely in phosphatidylinositol-mediated signaling and broader signal transduction pathways that govern cell cycle and survival checkpoints.

Cellular localization emerges naturally from the targeting modules. The soluble catalytic PTP core and the membrane-docking C2 domain together predict a cytoplasmic enzyme that transiently associates with membrane surfaces. Thus, the protein operates in the cytoplasm (GO:0005737), with dynamic recruitment to membrane-proximal cytoplasmic zones consistent with its soluble, membrane-associating design.

Mechanistically, I hypothesize that the N-terminal catalytic pocket engages both protein and lipid phosphates, while the C2-containing C-terminal region positions the enzyme on endomembranes and the plasma membrane to efficiently hydrolyze PI(3,4,5)P3. This membrane-tethered catalysis suppresses downstream kinase cascades and stabilizes cell polarity and genome integrity. Likely interaction partners are membrane-associated signaling assemblies and adaptors that present phosphoinositide-rich surfaces and scaffolds: insulin receptor complexes and PI3K products would be proximate; cytoskeletal and focal-adhesion organizers (tensins) would recruit the C2-bearing module; and polarity/scaffold proteins at membrane-cytoplasm interfaces would transiently bind to coordinate pathway attenuation.

Functional Summary

A cytoplasmic dual-specificity phosphatase that couples a cysteine-dependent catalytic core with a membrane-targeting module to remove phosphate groups from both protein and lipid substrates. By docking to membrane surfaces via a C2-containing region, it hydrolyzes signaling phosphoinositides to dampen growth-factor and insulin pathways, thereby constraining proliferation, sustaining proper cell-cycle and polarity control, and preserving genome integrity through attenuation of PI3K–Akt signaling.

UniProt Summary

Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-phosphorylated cellular substrates, as well as cellular and non-cellular phosphatidylinositol phosphates. PTEN is a bifunctional lipid- and protein-phosphatase which down-regulates PI3K-dependent signal transduction pathways. Translocates to the membrane of the endoplasmic reticulum in response to insulin depletion. The membrane-associated form is the major form found in cells (By similarity). Influences cell survival and proliferation, and is implicated in maintenance of cell polarity, control of the cell cycle, and genomic integrity.

InterPro Domains

Protein-tyrosine phosphatase-like (IPR029021, homologous_superfamily) — residues 1-187
Bifunctional phosphatidylinositol trisphosphate phosphatase/dual specificity phosphatase PTEN (IPR017361, family) — residues 1-403
Dual-specificity lipid and protein phosphatase (IPR051281, family) — residues 1-377
Tensin-type phosphatase domain (IPR029023, domain) — residues 14-185
Protein-tyrosine phosphatase, catalytic (IPR003595, domain) — residues 23-183
PTEN, phosphatase domain (IPR045101, domain) — residues 24-181
Tyrosine-specific protein phosphatases domain (IPR000387, domain) — residues 102-173
Protein-tyrosine phosphatase, active site (IPR016130, active_site) — residues 122-132
C2 domain superfamily (IPR035892, homologous_superfamily) — residues 188-349
Tensin phosphatase, C2 domain (IPR014020, domain) — residues 188-350

GO Terms

Molecular Function: molecular_function (GO:0003674), catalytic activity (GO:0003824), molecular function regulator activity (GO:0098772), binding (GO:0005488), molecular function inhibitor activity (GO:0140678), hydrolase activity (GO:0016787), protein-containing complex binding (GO:0044877), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), phosphoprotein phosphatase activity (GO:0004721), identical protein binding (GO:0042802), hydrolase activity, acting on ester bonds (GO:0016788), protein domain specific binding (GO:0019904), enzyme binding (GO:0019899), phosphoric ester hydrolase activity (GO:0042578), PDZ domain binding (GO:0030165), protease binding (GO:0002020), protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), ubiquitin-specific protease binding (GO:1990381), phosphatase activity (GO:0016791), phosphatidylinositol phosphate phosphatase activity (GO:0052866), inositol phosphate phosphatase activity (GO:0052745), phosphatidylinositol monophosphate phosphatase activity (GO:0052744), phosphatidylinositol bisphosphate phosphatase activity (GO:0034593), phosphatidylinositol trisphosphate phosphatase activity (GO:0034594), phosphatidylinositol-3-phosphate phosphatase activity (GO:0004438)

Biological Process: biological_process (GO:0008150), localization (GO:0051179), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), metabolic process (GO:0008152), negative regulation of biological process (GO:0048519), negative regulation of signaling (GO:0023057), nitrogen compound metabolic process (GO:0006807), negative regulation of multicellular organismal process (GO:0051241), regulation of multicellular organismal process (GO:0051239), negative regulation of metabolic process (GO:0009892), cell-cell signaling (GO:0007267), regulation of developmental process (GO:0050793), regulation of biological quality (GO:0065008), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), negative regulation of locomotion (GO:0040013), cellular response to stimulus (GO:0051716), regulation of signaling (GO:0023051), negative regulation of developmental process (GO:0051093), negative regulation of cellular process (GO:0048523), signal transduction (GO:0007165), regulation of locomotion (GO:0040012), response to abiotic stimulus (GO:0009628), positive regulation of signaling (GO:0023056), biosynthetic process (GO:0009058), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), organic substance metabolic process (GO:0071704), catabolic process (GO:0009056), cellular metabolic process (GO:0044237), small molecule metabolic process (GO:0044281), positive regulation of metabolic process (GO:0009893), regulation of molecular function (GO:0065009), negative regulation of response to stimulus (GO:0048585), cell communication (GO:0007154), primary metabolic process (GO:0044238), positive regulation of cellular process (GO:0048522), response to electrical stimulus (GO:0051602), negative regulation of signal transduction (GO:0009968), positive regulation of cell death (GO:0010942), negative regulation of cellular component organization (GO:0051129), regulation of cell motility (GO:2000145), regulation of response to stress (GO:0080134), regulation of signal transduction (GO:0009966), regulation of cell adhesion (GO:0030155), cellular lipid metabolic process (GO:0044255), negative regulation of epithelial to mesenchymal transition (GO:0010719), regulation of macromolecule metabolic process (GO:0060255), regulation of response to external stimulus (GO:0032101), carbohydrate metabolic process (GO:0005975), negative regulation of cell cycle process (GO:0010948), regulation of cellular component biogenesis (GO:0044087), phosphorus metabolic process (GO:0006793), regulation of catabolic process (GO:0009894), regulation of epithelial cell migration (GO:0010632), regulation of cell cycle (GO:0051726), negative regulation of cell adhesion (GO:0007162), negative regulation of macromolecule metabolic process (GO:0010605), cellular response to abiotic stimulus (GO:0071214), negative regulation of epithelial cell migration (GO:0010633), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cell differentiation (GO:0045595), cell surface receptor signaling pathway (GO:0007166), negative regulation of cell cycle (GO:0045786), regulation of cellular component organization (GO:0051128), organic substance catabolic process (GO:1901575), regulation of cell cycle process (GO:0010564), negative regulation of cell motility (GO:2000146), positive regulation of nitrogen compound metabolic process (GO:0051173), cellular carbohydrate metabolic process (GO:0044262), positive regulation of signal transduction (GO:0009967), organic hydroxy compound metabolic process (GO:1901615), negative regulation of cell communication (GO:0010648), regulation of catalytic activity (GO:0050790), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of molecular function (GO:0044093), organic substance biosynthetic process (GO:1901576), organonitrogen compound metabolic process (GO:1901564), small molecule catabolic process (GO:0044282), positive regulation of macromolecule metabolic process (GO:0010604), cell-cell signaling by wnt (GO:0198738), negative regulation of cell population proliferation (GO:0008285), organophosphate metabolic process (GO:0019637), protein metabolic process (GO:0019538), negative regulation of molecular function (GO:0044092), cell surface receptor signaling pathway involved in cell-cell signaling (GO:1905114), cellular biosynthetic process (GO:0044249), alcohol metabolic process (GO:0006066), regulation of protein stability (GO:0031647), negative regulation of cellular metabolic process (GO:0031324), macromolecule metabolic process (GO:0043170), cellular response to environmental stimulus (GO:0104004), regulation of cell population proliferation (GO:0042127), lipid metabolic process (GO:0006629), regulation of cell death (GO:0010941), regulation of cell communication (GO:0010646), positive regulation of cellular metabolic process (GO:0031325), negative regulation of cell differentiation (GO:0045596), regulation of DNA-binding transcription factor activity (GO:0051090), regulation of biosynthetic process (GO:0009889), regulation of cellular metabolic process (GO:0031323), positive regulation of cell communication (GO:0010647), regulation of primary metabolic process (GO:0080090), negative regulation of response to wounding (GO:1903035), positive regulation of catabolic process (GO:0009896), negative regulation of response to external stimulus (GO:0032102), regulation of mitotic cell cycle (GO:0007346), negative regulation of wound healing (GO:0061045), regulation of macromolecule biosynthetic process (GO:0010556), regulation of protein metabolic process (GO:0051246), regulation of cell-substrate adhesion (GO:0010810), regulation of programmed cell death (GO:0043067), Wnt signaling pathway (GO:0016055), phospholipid metabolic process (GO:0006644), regulation of cell migration (GO:0030334), cellular response to electrical stimulus (GO:0071257), negative regulation of smooth muscle cell proliferation (GO:0048662), regulation of cell-substrate junction organization (GO:0150116), glycerolipid biosynthetic process (GO:0045017), regulation of gene expression (GO:0010468), phosphorylated carbohydrate dephosphorylation (GO:0046838), inositol phosphate metabolic process (GO:0043647), regulation of smooth muscle cell proliferation (GO:0048660), macromolecule modification (GO:0043412), glycerolipid metabolic process (GO:0046486), alcohol catabolic process (GO:0046164), negative regulation of mitotic cell cycle (GO:0045930), organophosphate biosynthetic process (GO:0090407), negative regulation of phosphorus metabolic process (GO:0010563), lipid modification (GO:0030258), regulation of RNA metabolic process (GO:0051252), positive regulation of catalytic activity (GO:0043085), lipid biosynthetic process (GO:0008610), positive regulation of DNA-binding transcription factor activity (GO:0051091), negative regulation of cell-substrate adhesion (GO:0010812), negative regulation of catalytic activity (GO:0043086), regulation of response to wounding (GO:1903034), positive regulation of programmed cell death (GO:0043068), regulation of cell junction assembly (GO:1901888), negative regulation of protein metabolic process (GO:0051248), positive regulation of apoptotic signaling pathway (GO:2001235), phosphate-containing compound metabolic process (GO:0006796), negative regulation of intracellular signal transduction (GO:1902532), regulation of apoptotic signaling pathway (GO:2001233), negative regulation of cell junction assembly (GO:1901889), negative regulation of cell migration (GO:0030336), protein modification process (GO:0036211), organic hydroxy compound catabolic process (GO:1901616), regulation of cyclin-dependent protein kinase activity (GO:1904029), polyol metabolic process (GO:0019751), regulation of cell cycle phase transition (GO:1901987), regulation of cellular biosynthetic process (GO:0031326), positive regulation of protein metabolic process (GO:0051247), regulation of nucleobase-containing compound metabolic process (GO:0019219), positive regulation of cellular catabolic process (GO:0031331), protein stabilization (GO:0050821), regulation of transferase activity (GO:0051338), regulation of cellular catabolic process (GO:0031329), organophosphate catabolic process (GO:0046434), regulation of epithelial to mesenchymal transition (GO:0010717), regulation of intracellular signal transduction (GO:1902531), regulation of phosphorus metabolic process (GO:0051174), negative regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0045736), negative regulation of cell cycle phase transition (GO:1901988), negative regulation of cell-matrix adhesion (GO:0001953), regulation of phosphatidylinositol 3-kinase signaling (GO:0014066), regulation of apoptotic process (GO:0042981), regulation of vascular associated smooth muscle cell proliferation (GO:1904705), regulation of proteolysis (GO:0030162), negative regulation of cyclin-dependent protein kinase activity (GO:1904030), negative regulation of protein modification process (GO:0031400), regulation of RNA biosynthetic process (GO:2001141), regulation of cell-matrix adhesion (GO:0001952), phosphatidylinositol-mediated signaling (GO:0006470), regulation of ubiquitin-protein transferase activity (GO:0051438), inositol phosphate catabolic process (GO:0071545), canonical Wnt signaling pathway (GO:0060070), phospholipid biosynthetic process (GO:0008654), regulation of kinase activity (GO:0043549), regulation of protein kinase B signaling (GO:0051896), negative regulation of transferase activity (GO:0051348), regulation of ubiquitin-dependent protein catabolic process (GO:2000058), positive regulation of protein modification process (GO:0031401), phospholipid dephosphorylation (GO:0046839), regulation of wound healing (GO:0061041), inositol phosphate dephosphorylation (GO:0046855), negative regulation of MAPK cascade (GO:0043409), dephosphorylation (GO:0016311), regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), regulation of MAPK cascade (GO:0043408), positive regulation of apoptotic process (GO:0043065), positive regulation of transferase activity (GO:0051347), regulation of protein modification process (GO:0031399), negative regulation of mitotic cell cycle phase transition (GO:1901991), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), negative regulation of vascular associated smooth muscle cell proliferation (GO:1904706), glycerophospholipid biosynthetic process (GO:0046474), regulation of DNA-templated transcription (GO:0006355), regulation of phosphate metabolic process (GO:0019220), glycerophospholipid metabolic process (GO:0006650), negative regulation of protein kinase B signaling (GO:0051898), negative regulation of phosphatidylinositol 3-kinase signaling (GO:0014067), positive regulation of proteolysis (GO:0045862), regulation of mitotic cell cycle phase transition (GO:1901990), regulation of cell-substrate junction assembly (GO:0090109), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), regulation of extrinsic apoptotic signaling pathway (GO:2001236), polyol catabolic process (GO:0046174), regulation of cell cycle G1/S phase transition (GO:1902806), negative regulation of cell cycle G1/S phase transition (GO:1902807), negative regulation of phosphate metabolic process (GO:0045936), regulation of protein phosphorylation (GO:0001932), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134), negative regulation of phosphorylation (GO:0042326), regulation of protein kinase activity (GO:0045859), regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902041), positive regulation of protein modification by small protein conjugation or removal (GO:1903322), positive regulation of ubiquitin-protein transferase activity (GO:0051443), regulation of focal adhesion assembly (GO:0051893), regulation of nucleic acid-templated transcription (GO:1903506), regulation of ERK1 and ERK2 cascade (GO:0070372), regulation of phosphorylation (GO:0042325), negative regulation of protein phosphorylation (GO:0001933), regulation of protein modification by small protein conjugation or removal (GO:1903320), positive regulation of proteolysis involved in protein catabolic process (GO:1903052), negative regulation of kinase activity (GO:0033673), phosphatidylinositol dephosphorylation (GO:0046856), phosphatidylinositol metabolic process (GO:0046488), regulation of proteolysis involved in protein catabolic process (GO:1903050), negative regulation of ERK1 and ERK2 cascade (GO:0070373), regulation of G1/S transition of mitotic cell cycle (GO:2000045), regulation of ubiquitin protein ligase activity (GO:1904666), phosphatidylinositol biosynthetic process (GO:0006661), regulation of protein serine/threonine kinase activity (GO:0071900), regulation of protein ubiquitination (GO:0031396), negative regulation of peptidyl-serine phosphorylation (GO:0033137), regulation of peptidyl-serine phosphorylation (GO:0033135), negative regulation of protein kinase activity (GO:0006469), positive regulation of protein ubiquitination (GO:0031398), negative regulation of protein serine/threonine kinase activity (GO:0071901)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), side of membrane (GO:0098552), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), apical part of cell (GO:0045177), cell projection (GO:0042995), membrane (GO:0016020), cytosol (GO:0005829), cytoplasm (GO:0005737), cell periphery (GO:0071944), membrane-enclosed lumen (GO:0031974), nucleoplasm (GO:0005654), plasma membrane region (GO:0098590), organelle lumen (GO:0043233), intracellular organelle (GO:0043229), cytoplasmic side of membrane (GO:0098562), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), cytoplasmic side of plasma membrane (GO:0009898), intracellular membrane-bounded organelle (GO:0043231), intracellular organelle lumen (GO:0070013), nuclear lumen (GO:0031981), nucleus (GO:0005634)

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Deep Research Bioreason Rl

(PTEN-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 03:09 AM

Organism: Homo sapiens

Sequence:

MTAIIKEIVSRNKRRYQEDGFDLDLTYIYPNIIAMGFPAERLEGVYRNNIDDVVRFLDSKHKNHYKIYNLCAERHYDTAKFNCRVAQYPFEDHNPPQLELIKPFCEDLDQWLSEDDNHVAAIHCKAGKGRTGVMICAYLLHRGKFLKAQEALDFYGEVRTRDKKGVTIPSQRRYVYYYSYLLKNHLDYRPVALLFHKMMFETIPMFSGGTCNPQFVVCQLKVKIYSSNSGPTRREDKFMYFEFPQPLPVCGDIKVEFFHKQNKMLKKDKMFHFWVNTFFIPGPEETSEKVENGSLCDQEIDSICSIERADNDKEYLVLTLTKNDLDKANKDKANRYFSPNFKVKLYFTKTVEEPSNPEASSSTSVTPDVSDNEPDHYRYSDTTDSDPENEPFDEDQHTQITKV

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

Protein-tyrosine phosphatase-like (IPR029021, homologous_superfamily) — residues 1-187
Bifunctional phosphatidylinositol trisphosphate phosphatase/dual specificity phosphatase PTEN (IPR017361, family) — residues 1-403
Dual-specificity lipid and protein phosphatase (IPR051281, family) — residues 1-377
Tensin-type phosphatase domain (IPR029023, domain) — residues 14-185
Protein-tyrosine phosphatase, catalytic (IPR003595, domain) — residues 23-183
PTEN, phosphatase domain (IPR045101, domain) — residues 24-181
Tyrosine-specific protein phosphatases domain (IPR000387, domain) — residues 102-173
Protein-tyrosine phosphatase, active site (IPR016130, active_site) — residues 122-132
C2 domain superfamily (IPR035892, homologous_superfamily) — residues 188-349
Tensin phosphatase, C2 domain (IPR014020, domain) — residues 188-350

GO Terms

Generated by BioReason

Deep Research Falcon

(PTEN-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
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start_time: '2025-12-24T10:19:48.062193'
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: PTEN
gene_symbol: PTEN
uniprot_accession: P60484
protein_description: 'RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase
and dual-specificity protein phosphatase PTEN {ECO:0000305|PubMed:9256433, ECO:0000305|PubMed:9811831};
EC=3.1.3.16 {ECO:0000269|PubMed:9256433}; EC=3.1.3.48 {ECO:0000269|PubMed:9187108,
ECO:0000269|PubMed:9256433}; EC=3.1.3.67 {ECO:0000269|PubMed:16824732, ECO:0000269|PubMed:9811831};
AltName: Full=Inositol polyphosphate 3-phosphatase {ECO:0000305|PubMed:11418101,
ECO:0000305|PubMed:9593664}; EC=3.1.3.- {ECO:0000305|PubMed:11418101, ECO:0000305|PubMed:9593664};
AltName: Full=Mutated in multiple advanced cancers 1; AltName: Full=Phosphatase
and tensin homolog;'
gene_info: Name=PTEN; Synonyms=MMAC1, TEP1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the PTEN phosphatase protein family.
protein_domains: Bifunc_PIno_P3_Pase/Pase_PTEN. (IPR017361); C2_domain_sf. (IPR035892);
Dual-spec_lipid-protein_phosph. (IPR051281); Prot-tyrosine_phosphatase-like. (IPR029021);
PTP_PTEN. (IPR045101)
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citation_count: 19

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P60484
Protein Description: RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN {ECO:0000305|PubMed:9256433, ECO:0000305|PubMed:9811831}; EC=3.1.3.16 {ECO:0000269|PubMed:9256433}; EC=3.1.3.48 {ECO:0000269|PubMed:9187108, ECO:0000269|PubMed:9256433}; EC=3.1.3.67 {ECO:0000269|PubMed:16824732, ECO:0000269|PubMed:9811831}; AltName: Full=Inositol polyphosphate 3-phosphatase {ECO:0000305|PubMed:11418101, ECO:0000305|PubMed:9593664}; EC=3.1.3.- {ECO:0000305|PubMed:11418101, ECO:0000305|PubMed:9593664}; AltName: Full=Mutated in multiple advanced cancers 1; AltName: Full=Phosphatase and tensin homolog;
Gene Information: Name=PTEN; Synonyms=MMAC1, TEP1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the PTEN phosphatase protein family.
Key Domains: Bifunc_PIno_P3_Pase/Pase_PTEN. (IPR017361); C2_domain_sf. (IPR035892); Dual-spec_lipid-protein_phosph. (IPR051281); Prot-tyrosine_phosphatase-like. (IPR029021); PTP_PTEN. (IPR045101)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PTEN" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'PTEN' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene PTEN (gene ID: PTEN, UniProt: P60484) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P60484
Protein Description: RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN {ECO:0000305|PubMed:9256433, ECO:0000305|PubMed:9811831}; EC=3.1.3.16 {ECO:0000269|PubMed:9256433}; EC=3.1.3.48 {ECO:0000269|PubMed:9187108, ECO:0000269|PubMed:9256433}; EC=3.1.3.67 {ECO:0000269|PubMed:16824732, ECO:0000269|PubMed:9811831}; AltName: Full=Inositol polyphosphate 3-phosphatase {ECO:0000305|PubMed:11418101, ECO:0000305|PubMed:9593664}; EC=3.1.3.- {ECO:0000305|PubMed:11418101, ECO:0000305|PubMed:9593664}; AltName: Full=Mutated in multiple advanced cancers 1; AltName: Full=Phosphatase and tensin homolog;
Gene Information: Name=PTEN; Synonyms=MMAC1, TEP1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the PTEN phosphatase protein family.
Key Domains: Bifunc_PIno_P3_Pase/Pase_PTEN. (IPR017361); C2_domain_sf. (IPR035892); Dual-spec_lipid-protein_phosph. (IPR051281); Prot-tyrosine_phosphatase-like. (IPR029021); PTP_PTEN. (IPR045101)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PTEN" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene PTEN (gene ID: PTEN, UniProt: P60484) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Human PTEN (UniProt P60484)

Verification of target identity and domain architecture
- Gene/protein identity: The requested target is human PTEN (phosphatase and tensin homolog), a 403–amino-acid dual-specificity phosphatase that belongs to the PTEN phosphatase family. Canonical domains include an N‑terminal phosphoinositide-binding region, the catalytic phosphatase domain containing the active site (approx. residues 123–130), a C2 domain that mediates membrane association, and a C‑terminal tail with a PDZ-binding motif. Noncanonical, N‑terminally extended isoforms (PTEN‑L/α and PTEN‑β) exist and retain the canonical PTEN core. These features align with the UniProt P60484 description and the stated family/domains. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.1093/hmg/ddaa127, Jun 2020) (yehia2019ptenopathiesfrombiological pages 1-2, yehia2019ptenopathiesfrombiological pages 4-5, yehia2020ptenhamartomatumour pages 5-6)

Key concepts and definitions: catalytic activities and biochemical specificity
- Enzymatic class and reaction: PTEN is a dual-specificity phosphatase with a primary lipid phosphatase activity that hydrolyzes phosphatidylinositol 3,4,5‑trisphosphate (PIP3) to PIP2 at the D3 position, thereby antagonizing PI3K signaling. PTEN also has protein phosphatase activity toward select protein substrates, but recent functional dissection in melanoma indicates the lipid phosphatase function predominates for tumor suppression in vivo. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (yehia2019ptenopathiesfrombiological pages 1-2, xu2024ptenlipidphosphatase pages 23-30)
- Substrate context and site of action: PTEN’s lipid phosphatase function requires membrane engagement via the C2 domain and N‑terminal phosphoinositide interactions, positioning the catalytic site to dephosphorylate PIP3 in the inner leaflet of the plasma membrane. (https://doi.org/10.1172/JCI121277, Jan 2019) (yehia2019ptenopathiesfrombiological pages 1-2)

Pathway roles and current understanding
- Core signaling: By converting PIP3→PIP2, PTEN reduces AKT recruitment/activation and downstream mTOR signaling, restraining cell growth, survival, metabolism, and translation. Loss or inactivation of PTEN elevates AKT/mTOR signaling and alters transcriptional and metabolic programs. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (yehia2019ptenopathiesfrombiological pages 1-2, xu2024ptenlipidphosphatase pages 23-30)
- 2024 mechanistic update: In melanoma models, restoration of PTEN’s lipid phosphatase activity suppressed proliferation, invasion, and tumor growth primarily through inhibition of an AKT/mTOR/FRA1 axis; phosphoproteomics supported the dominance of lipid phosphatase–mediated network changes over other proposed noncanonical functions. (https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (xu2024ptenlipidphosphatase pages 23-30)

Subcellular localization and nuclear functions
- Cytosol/membrane: PTEN localizes to cytosol and the inner plasma membrane for lipid dephosphorylation that opposes PI3K. (https://doi.org/10.1172/JCI121277, Jan 2019) (yehia2019ptenopathiesfrombiological pages 1-2)
- Nuclear functions: Nuclear PTEN contributes to genomic stability, DNA double-strand break repair, cell-cycle control, chromosomal architecture, and regulation of rDNA transcription. Nuclear localization is regulated by post‑translational modifications (PTMs) and ubiquitin-dependent trafficking. (https://doi.org/10.1093/hmg/ddaa127, Jun 2020; https://doi.org/10.3389/or.2024.1430237, Jul 2024) (yehia2020ptenhamartomatumour pages 5-6, li2024posttranslationalmodificationof pages 8-8)

Regulation, post-translational modifications, and interactors
- Phosphorylation: C‑terminal tail phosphorylation regulates PTEN’s conformation, membrane association, and catalytic activity, generally modulating stability and activity in a context-dependent manner. (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 8-8)
- Ubiquitination and nuclear import: Mono- and polyubiquitination control PTEN stability and subcellular localization; specific ubiquitin machinery promotes nuclear import, where PTEN contributes to chromosome stability (e.g., interactions with centromeric proteins). (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 8-8, li2024posttranslationalmodificationof pages 5-6)
- Oxidation: Reactive oxygen species can oxidize PTEN, disrupting membrane association and lipid phosphatase function; antioxidant systems (e.g., peroxiredoxins) can preserve PTEN activity. (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 5-6)
- SUMOylation/neddylation: SUMO and NEDD8 modifications further influence PTEN localization and activity, including promoting nuclear entry under certain metabolic conditions. (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 8-8)
- Scaffolding and membrane recruitment: PDZ-domain scaffolds (e.g., MAGI proteins) recruit PTEN to junctional complexes and membrane subdomains to efficiently deplete PIP3. (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 8-8)

Disease relevance: germline and somatic
- Germline: Pathogenic germline PTEN variants cause PTEN hamartoma tumor syndrome (PHTS), an autosomal dominant cancer-predisposition and overgrowth spectrum with elevated risks of breast, thyroid, endometrial, and other cancers; large germline deletions account for an estimated 3–10% of PHTS. Identification warrants enhanced surveillance and genetic counseling. (https://doi.org/10.1093/hmg/ddaa127, Jun 2020; https://doi.org/10.1172/JCI121277, Jan 2019) (yehia2020ptenhamartomatumour pages 5-6, yehia2019ptenopathiesfrombiological pages 4-5, yehia2019ptenopathiesfrombiological pages 1-2)
- Somatic: PTEN is among the most frequently altered tumor suppressors across sporadic cancers; functional analyses confirm that loss of lipid phosphatase activity drives AKT/mTOR activation and oncogenesis in several settings, including melanoma. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (yehia2019ptenopathiesfrombiological pages 1-2, xu2024ptenlipidphosphatase pages 23-30)

Recent developments (emphasis 2023–2024) and expert perspectives
- Functional dominance of lipid phosphatase activity in melanoma (2024): Genetic rescue and phosphoproteomics demonstrate that PTEN’s lipid phosphatase activity is the principal mediator of tumor suppression via AKT/mTOR/FRA1 control, informing expectations for pathway-directed therapies in PTEN-deficient melanomas. (https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (xu2024ptenlipidphosphatase pages 23-30)
- PTEN proteoform and PTM-centric regulation (2024): Mechanistic review highlights how multi-site phosphorylation, ubiquitination, oxidation, SUMOylation, and neddylation dynamically tune PTEN’s abundance, conformation, localization (including nuclear import), and activity. This regulatory complexity underlies variable PTEN function across tissues and disease states. (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 8-8, li2024posttranslationalmodificationof pages 5-6)

Current applications and real-world implementations
- Diagnostic assessment: PTEN status is commonly assessed by next-generation sequencing (NGS) to detect mutations and copy-number loss. Immunohistochemistry (IHC) is used in clinical practice to gauge PTEN protein loss as a pragmatic screening tool when NGS material is limited, with confirmatory molecular testing where appropriate. These uses are framed within gene‑informed management for PHTS and pathway‑informed therapy considerations in sporadic cancers. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.3389/or.2024.1430237, Jul 2024) (yehia2019ptenopathiesfrombiological pages 1-2, li2024posttranslationalmodificationof pages 8-8)
- Therapeutic implications: PTEN loss indicates upregulated PI3K–AKT–mTOR signaling. Although direct PTEN restoration is not a current therapy, pathway inhibitors (e.g., AKT/mTOR inhibitors) are of interest; however, network feedback and context‑specific dependencies necessitate careful clinical evaluation. (https://doi.org/10.1172/JCI121277, Jan 2019) (yehia2019ptenopathiesfrombiological pages 8-9, yehia2019ptenopathiesfrombiological pages 1-2)

Relevant statistics and data from recent studies
- Functional evidence rather than frequency summary: 2024 functional cancer research demonstrates that PTEN lipid phosphatase restoration can suppress melanoma growth and invasion via AKT/mTOR/FRA1, supporting the centrality of PI3K pathway dependence in PTEN‑deficient tumors. (https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (xu2024ptenlipidphosphatase pages 23-30)
- Germline structural variant contribution in PHTS: Reviews report that large PTEN deletions comprise approximately 3–10% of PHTS cases, underscoring the need for copy‑number assessment in genetic testing workflows. (https://doi.org/10.1093/hmg/ddaa127, Jun 2020) (yehia2020ptenhamartomatumour pages 5-6)

Expert analysis
- Mechanistic consensus: Across authoritative sources, PTEN’s tumor suppressor function is primarily mediated by its lipid phosphatase activity restraining PI3K–AKT–mTOR signaling, with additional nuclear roles stabilizing the genome and regulating transcriptional programs. This duality explains both the metabolic/proliferative phenotypes of PTEN deficiency and the genomic instability seen in PHTS spectrum disorders. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.1093/hmg/ddaa127, Jun 2020; https://doi.org/10.1158/0008-5472.can-23-1730, Jan 2024) (yehia2019ptenopathiesfrombiological pages 1-2, yehia2020ptenhamartomatumour pages 5-6, xu2024ptenlipidphosphatase pages 23-30)
- Regulatory layers shape phenotype: PTMs (phosphorylation, ubiquitination, oxidation, SUMO/neddylation) and scaffolding interactions modulate PTEN’s localization, stability, and conformational state, providing plausible mechanistic bases for tissue‑specific effects and variable penetrance in disease. (https://doi.org/10.3389/or.2024.1430237, Jul 2024) (li2024posttranslationalmodificationof pages 8-8, li2024posttranslationalmodificationof pages 5-6)

Embedded summary table

Topic	Key points (1–3 bullets)	Prime sources (journal, year)	URL
Identity & domains	- PTEN: 403 aa, PIP2‑binding region; phosphatase (catalytic) domain; C2 domain; C‑terminal tail with PDZ motif - N‑terminally extended isoforms (PTEN‑L/α, PTEN‑β) exist	J Clin Invest, 2019; Hum Mol Genet, 2020 (reviews) (yehia2019ptenopathiesfrombiological pages 4-5, yehia2020ptenhamartomatumour pages 5-6)	https://doi.org/10.1172/JCI121277 https://doi.org/10.1093/hmg/ddaa127 (yehia2019ptenopathiesfrombiological pages 4-5, yehia2020ptenhamartomatumour pages 5-6)
Enzymatic activity & substrates	- Dual‑specificity phosphatase: lipid phosphatase (PIP3 → PIP2) and protein dephosphorylation - Catalytic pocket ≈ residues 123–130; lipid activity is key for tumor suppression	Cancer Research, 2024; J Clin Invest, 2019 (xu2024ptenlipidphosphatase pages 23-30, yehia2019ptenopathiesfrombiological pages 4-5)	https://doi.org/10.1158/0008-5472.can-23-1730 https://doi.org/10.1172/JCI121277 (xu2024ptenlipidphosphatase pages 23-30, yehia2019ptenopathiesfrombiological pages 4-5)
Core pathway roles (PI3K–AKT–mTOR)	- Antagonizes PI3K→AKT→mTOR by depleting PIP3; loss → AKT/mTOR activation and increased proliferation/metabolism - PTEN loss contributes to immunomodulation and therapy resistance	J Clin Invest, 2019; Cancer Research, 2024 (yehia2019ptenopathiesfrombiological pages 1-2, xu2024ptenlipidphosphatase pages 23-30)	https://doi.org/10.1172/JCI121277 https://doi.org/10.1158/0008-5472.can-23-1730 (yehia2019ptenopathiesfrombiological pages 1-2, xu2024ptenlipidphosphatase pages 23-30)
Subcellular localization & nuclear functions	- Active at plasma membrane/cytosol for lipid phosphatase function - Nuclear PTEN roles: genomic stability, DNA‑damage response, cell‑cycle control, rDNA transcription; localization regulated by PTMs/ubiquitination	Hum Mol Genet, 2020; Oncology Reviews, 2024 (yehia2020ptenhamartomatumour pages 5-6, li2024posttranslationalmodificationof pages 8-8)	https://doi.org/10.1093/hmg/ddaa127 https://doi.org/10.3389/or.2024.1430237 (yehia2020ptenhamartomatumour pages 5-6, li2024posttranslationalmodificationof pages 8-8)
Regulation by PTMs (phospho, ubiq, ox, SUMO/neddylation)	- C‑terminal phosphorylation modulates stability/activity; ubiquitination controls degradation and nuclear import - Oxidation inactivates lipid activity; SUMOylation/neddylation affect localization; exosomal miRNAs modulate PTEN levels	Oncology Reviews, 2024 (mechanistic review) (li2024posttranslationalmodificationof pages 8-8, li2024posttranslationalmodificationof pages 5-6)	https://doi.org/10.3389/or.2024.1430237 (li2024posttranslationalmodificationof pages 8-8, li2024posttranslationalmodificationof pages 5-6)
Disease relevance (somatic cancers; PHTS germline)	- Germline PTEN pathogenic variants → PTEN Hamartoma Tumor Syndrome (PHTS) with elevated breast, thyroid, endometrial cancer risk; variable penetrance - Somatic PTEN loss/mutation common across cancers (melanoma, prostate, glioblastoma, others)	J Clin Invest, 2019; Cancer Research, 2024 (yehia2019ptenopathiesfrombiological pages 4-5, xu2024ptenlipidphosphatase pages 23-30)	https://doi.org/10.1172/JCI121277 https://doi.org/10.1158/0008-5472.can-23-1730 (yehia2019ptenopathiesfrombiological pages 4-5, xu2024ptenlipidphosphatase pages 23-30)
Clinical applications (IHC / NGS; therapy implications)	- PTEN status assessed by IHC and NGS in diagnostics; IHC can be pragmatic when NGS not possible - PTEN loss guides genetic counseling for PHTS and may inform use of PI3K/AKT/mTOR pathway inhibitors (clinical exploration)	J Clin Invest, 2019; Oncology Reviews, 2024 (yehia2019ptenopathiesfrombiological pages 1-2, li2024posttranslationalmodificationof pages 8-8)	https://doi.org/10.1172/JCI121277 https://doi.org/10.3389/or.2024.1430237 (yehia2019ptenopathiesfrombiological pages 1-2, li2024posttranslationalmodificationof pages 8-8)
Recent statistics/findings (2023–2024)	- 2024: PTEN lipid phosphatase activity shown essential to suppress melanoma via AKT/mTOR/FRA1 axis (functional rescue/ phosphoproteomics) - Germline PHTS detection rates vary; large deletions ~3–10% of PHTS cases; reported germline detection ranges widely in reviews	Cancer Research, 2024; Hum Mol Genet, 2020 (xu2024ptenlipidphosphatase pages 23-30, yehia2020ptenhamartomatumour pages 5-6)	https://doi.org/10.1158/0008-5472.can-23-1730 https://doi.org/10.1093/hmg/ddaa127 (xu2024ptenlipidphosphatase pages 23-30, yehia2020ptenhamartomatumour pages 5-6)

Table: A concise, source‑linked table summarizing identity, enzymatic function, pathway roles, localization, regulation, disease relevance, clinical uses, and recent 2023–2024 findings for human PTEN (UniProt P60484), with citations to the core evidence used.

Notes on scope and limitations of the present synthesis
- The report prioritizes 2023–2024 peer‑reviewed sources and authoritative recent reviews. We focused on sources available in the provided context with accessible URLs and publication dates. Some pan‑cancer frequency statistics from large clinicogenomic cohorts are beyond the scope of the included evidence set; where high‑level prevalence statements are made, they derive from consensus reviews (2019–2020) rather than a specific 2023–2024 frequency table. (https://doi.org/10.1172/JCI121277, Jan 2019; https://doi.org/10.1093/hmg/ddaa127, Jun 2020) (yehia2019ptenopathiesfrombiological pages 1-2, yehia2020ptenhamartomatumour pages 5-6)

References

(yehia2019ptenopathiesfrombiological pages 1-2): Lamis Yehia, Joanne Ngeow, and Charis Eng. Pten-opathies: from biological insights to evidence-based precision medicine. The Journal of clinical investigation, 129 2:452-464, Jan 2019. URL: https://doi.org/10.1172/jci121277, doi:10.1172/jci121277. This article has 199 citations.
(yehia2019ptenopathiesfrombiological pages 4-5): Lamis Yehia, Joanne Ngeow, and Charis Eng. Pten-opathies: from biological insights to evidence-based precision medicine. The Journal of clinical investigation, 129 2:452-464, Jan 2019. URL: https://doi.org/10.1172/jci121277, doi:10.1172/jci121277. This article has 199 citations.
(yehia2020ptenhamartomatumour pages 5-6): Lamis Yehia and Charis Eng. Pten hamartoma tumour syndrome: what happens when there is no pten germline mutation? Human molecular genetics, 29:R150-R157, Jun 2020. URL: https://doi.org/10.1093/hmg/ddaa127, doi:10.1093/hmg/ddaa127. This article has 24 citations and is from a domain leading peer-reviewed journal.
(xu2024ptenlipidphosphatase pages 23-30): Xiaonan Xu, Ilah Bok, Neel Jasani, Kaizhen Wang, Manon Chadourne, Nicol Mecozzi, Ou Deng, Eric A. Welsh, Fumi Kinose, Uwe Rix, and Florian A. Karreth. Pten lipid phosphatase activity suppresses melanoma formation by opposing an akt/mtor/fra1 signaling axis. Cancer research, 84:OF1-OF17, Jan 2024. URL: https://doi.org/10.1158/0008-5472.can-23-1730, doi:10.1158/0008-5472.can-23-1730. This article has 16 citations and is from a highest quality peer-reviewed journal.
(li2024posttranslationalmodificationof pages 8-8): Xiao Li, Pu Yang, Xiaoli Hou, and Shaoping Ji. Post-translational modification of pten protein: quantity and activity. Oncology Reviews, Jul 2024. URL: https://doi.org/10.3389/or.2024.1430237, doi:10.3389/or.2024.1430237. This article has 6 citations.
(li2024posttranslationalmodificationof pages 5-6): Xiao Li, Pu Yang, Xiaoli Hou, and Shaoping Ji. Post-translational modification of pten protein: quantity and activity. Oncology Reviews, Jul 2024. URL: https://doi.org/10.3389/or.2024.1430237, doi:10.3389/or.2024.1430237. This article has 6 citations.
(yehia2019ptenopathiesfrombiological pages 8-9): Lamis Yehia, Joanne Ngeow, and Charis Eng. Pten-opathies: from biological insights to evidence-based precision medicine. The Journal of clinical investigation, 129 2:452-464, Jan 2019. URL: https://doi.org/10.1172/jci121277, doi:10.1172/jci121277. This article has 199 citations.

Citations

yehia2019ptenopathiesfrombiological pages 1-2
xu2024ptenlipidphosphatase pages 23-30
li2024posttranslationalmodificationof pages 8-8
li2024posttranslationalmodificationof pages 5-6
yehia2020ptenhamartomatumour pages 5-6
yehia2019ptenopathiesfrombiological pages 4-5
yehia2019ptenopathiesfrombiological pages 8-9
https://doi.org/10.1172/JCI121277,
https://doi.org/10.1093/hmg/ddaa127,
https://doi.org/10.1158/0008-5472.can-23-1730,
https://doi.org/10.3389/or.2024.1430237,
https://doi.org/10.1172/JCI121277
https://doi.org/10.1093/hmg/ddaa127
https://doi.org/10.1158/0008-5472.can-23-1730
https://doi.org/10.1172/JCI121277
https://doi.org/10.1172/JCI121277
https://doi.org/10.1158/0008-5472.can-23-1730
https://doi.org/10.1093/hmg/ddaa127
https://doi.org/10.3389/or.2024.1430237
https://doi.org/10.3389/or.2024.1430237
https://doi.org/10.1172/JCI121277
https://doi.org/10.3389/or.2024.1430237
https://doi.org/10.1158/0008-5472.can-23-1730
https://doi.org/10.1093/hmg/ddaa127
https://doi.org/10.1172/jci121277,

Bioreason Rl Review

(PTEN-bioreason-rl-review.md)

BioReason-Pro RL Review: PTEN (human)

Source: PTEN-deep-research-bioreason-rl.md

Correctness: 5/5
Completeness: 4/5

Functional Summary Review

The BioReason functional summary states:

A cytoplasmic dual-specificity phosphatase that couples a cysteine-dependent catalytic core with a membrane-targeting module to remove phosphate groups from both protein and lipid substrates. By docking to membrane surfaces via a C2-containing region, it hydrolyzes signaling phosphoinositides to dampen growth-factor and insulin pathways, thereby constraining proliferation, sustaining proper cell-cycle and polarity control, and preserving genome integrity through attenuation of PI3K-Akt signaling.

This is an excellent summary that accurately captures PTEN's core biology. The curated review describes PTEN as "a critical tumor suppressor encoding a dual-specificity phosphatase with both lipid and protein phosphatase activities" whose "primary and essential tumor suppressor function is as a phosphatidylinositol-3,4,5-trisphosphate (PIP3) 3-phosphatase that dephosphorylates PIP3 to PIP2, thereby antagonizing PI3K/AKT/mTOR signaling."

BioReason correctly identifies:
1. Dual-specificity phosphatase activity (protein and lipid substrates)
2. The PTP catalytic domain with cysteine-based mechanism
3. The C2 membrane-targeting domain
4. PI3K-Akt pathway attenuation as the core biological function
5. Roles in proliferation control and cell polarity
6. Cytoplasmic localization with membrane association

The mention of "genome integrity" is also appropriate, as PTEN has roles in DNA repair and maintaining chromosomal stability.

Minor gaps:
1. The nuclear pool of PTEN and its nuclear functions are not mentioned
2. PTEN's protein phosphatase activity toward specific substrates (FAK, SHC) is not detailed
3. The Wnt signaling regulation role from the curated review is absent
4. PTEN's scaffolding functions independent of catalytic activity are not captured

Comparison with interpro2go:

The interpro2go annotations from IPR003595 (PTP catalytic domain) and IPR045101 (PTEN phosphatase domain) would map to protein tyrosine phosphatase activity and phosphatidylinositol phosphate phosphatase activity. BioReason arrives at exactly these functions and adds valuable mechanistic context about the C2 domain membrane-targeting and PI3K pathway attenuation. This represents genuine value-add over raw interpro2go output.

Notes on thinking trace

The trace demonstrates excellent reasoning through the layered phosphatase signatures and the C2 domain. The identification of both lipid and protein phosphatase activities from the domain architecture is well-supported. The mechanistic hypothesis about membrane-tethered catalysis of PI(3,4,5)P3 is accurate.

📄 View Raw YAML

id: P60484
gene_symbol: PTEN
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PTEN (Phosphatase and Tensin Homolog) is a critical tumor 
  suppressor encoding a dual-specificity phosphatase with both lipid and protein
  phosphatase activities. Its primary and essential tumor suppressor function is
  as a phosphatidylinositol-3,4,5-trisphosphate (PIP3) 3-phosphatase that 
  dephosphorylates PIP3 to PIP2, thereby antagonizing PI3K/AKT/mTOR signaling. 
  PTEN also exhibits protein phosphatase activity against serine, threonine, and
  tyrosine residues, though the lipid phosphatase activity is the critical 
  determinant of tumor suppression. Nuclear PTEN contributes to genomic 
  stability and cell cycle control. PTEN localizes to the plasma membrane, 
  cytosol, and nucleus, with membrane localization mediated by its C2 domain and
  PDZ-binding motif interactions with scaffold proteins like MAGI-2. Germline 
  mutations cause PTEN Hamartoma Tumor Syndrome (PHTS/Cowden disease), while 
  somatic mutations occur frequently across many cancer types.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN nuclear localization is well-established. Nuclear PTEN has 
        distinct roles in genomic stability, DNA damage response, and cell cycle
        control, regulated by PTMs and ubiquitin-dependent trafficking.
      action: ACCEPT
      reason: Nuclear localization is a conserved and functionally important 
        feature of PTEN, supported by extensive experimental evidence and 
        phylogenetic conservation.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner
        - reference_id: PMID:17218261
          supporting_text: Ubiquitination regulates PTEN nuclear import and 
            tumor suppression
        - reference_id: file:human/PTEN/PTEN-deep-research-falcon.md
          supporting_text: See deep research file for comprehensive analysis
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Plasma membrane localization is essential for PTEN's core lipid 
        phosphatase function. PTEN is recruited to the membrane via its C2 
        domain and PDZ-binding motif interactions with scaffold proteins like 
        MAGI-2.
      action: ACCEPT
      reason: Plasma membrane localization is the primary site of PTEN's lipid 
        phosphatase activity against PIP3, essential for its tumor suppressor 
        function.
      supported_by:
        - reference_id: PMID:10760291
          supporting_text: PTEN binds to MAGI-2 through an interaction between 
            the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. 
            MAGI-2 enhances the ability of PTEN to suppress Akt activation.
  - term:
      id: GO:0042995
      label: cell projection
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN localizes to cell projections, consistent with its role in 
        regulating cell motility through PI3K signaling modulation at the 
        leading edge of cells.
      action: ACCEPT
      reason: PTEN localization to cell projections is consistent with its role 
        in regulating directed cell migration through local PIP3 levels, a 
        phylogenetically conserved feature.
  - term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN is a central component of PI3K/AKT signaling, acting as the 
        primary negative regulator by dephosphorylating PIP3 to PIP2.
      action: ACCEPT
      reason: This is the core pathway in which PTEN functions. By removing 
        PIP3, PTEN prevents AKT recruitment and activation, making this a core 
        annotation.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: ectopic expression of the phosphatase in 
            PTEN-deficient tumor cell lines resulted in the inhibition of 
            protein kinase (PK) B/Akt and regulation of cell survival
  - term:
      id: GO:0051896
      label: regulation of phosphatidylinositol 3-kinase/protein kinase B signal
        transduction
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN negatively regulates PI3K/AKT signaling via its lipid 
        phosphatase activity. This is redundant with GO:0051898 (negative 
        regulation) which is more specific.
      action: MODIFY
      reason: While accurate, GO:0051898 (negative regulation of PI3K/AKT 
        signaling) is more specific to PTEN's actual role as an antagonist of 
        this pathway.
      proposed_replacement_terms:
        - id: GO:0051898
          label: negative regulation of phosphatidylinositol 3-kinase/protein 
            kinase B signal transduction
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN is found in the cytosol where it can exist in an inactive 
        closed conformation. Cytosolic PTEN can be recruited to membranes for 
        its lipid phosphatase function.
      action: ACCEPT
      reason: Cytosolic localization is well-established for PTEN and represents
        a reservoir pool that can be recruited to membranes upon appropriate 
        signals.
  - term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN dephosphorylates phosphatidylinositols at the D3 position, 
        with primary activity against PIP3 and PI(3,4)P2.
      action: ACCEPT
      reason: This is a core biological process annotation that accurately 
        describes PTEN's primary enzymatic function.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: Characterization of the lipid phosphatase activity of
            PTEN demonstrates that it shows specificity for 
            phosphatidylinositols phosphorylated at the 3 position.
  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN exhibits protein tyrosine phosphatase activity as part of 
        its dual-specificity phosphatase function, though the lipid phosphatase 
        activity is the critical determinant of tumor suppression.
      action: ACCEPT
      reason: PTEN has documented protein tyrosine phosphatase activity. While 
        secondary to its lipid phosphatase function for tumor suppression, this 
        is a legitimate enzymatic activity.
      supported_by:
        - reference_id: PMID:9256433
          supporting_text: recombinant P-TEN dephosphorylated protein and 
            peptide substrates phosphorylated on serine, threonine, and tyrosine
            residues, indicating that P-TEN is a dual-specificity phosphatase
  - term:
      id: GO:0016314
      label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This is PTEN's primary enzymatic activity - dephosphorylating 
        PIP3 at the D3 position to produce PIP2. This activity is essential for 
        its tumor suppressor function.
      action: ACCEPT
      reason: This is the core molecular function of PTEN. The lipid phosphatase
        activity against PIP3 is the critical determinant of PTEN's tumor 
        suppressor function.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: a missense mutation in PTEN, PTEN-G129E, which is 
            observed in two Cowden disease kindreds, specifically ablates the 
            ability of PTEN to recognize inositol phospholipids as a substrate, 
            suggesting that loss of the lipid phosphatase activity is 
            responsible for the etiology of the disease
  - term:
      id: GO:0048870
      label: cell motility
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PTEN regulates cell motility through its effects on PIP3 levels, 
        which control cell polarity and directed migration. Loss of PTEN 
        enhances cell motility.
      action: KEEP_AS_NON_CORE
      reason: While PTEN's regulation of cell motility is well-established, this
        is a downstream effect of its lipid phosphatase activity rather than a 
        core function. The core function is PIP3 dephosphorylation.
      supported_by:
        - reference_id: PMID:9616126
          supporting_text: Inhibition of cell migration, spreading, and focal 
            adhesions by tumor suppressor PTEN
  - term:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PTEN has dual-specificity protein phosphatase activity including 
        activity against serine/threonine residues.
      action: ACCEPT
      reason: This is supported by experimental evidence showing PTEN 
        dephosphorylates serine/threonine substrates.
      supported_by:
        - reference_id: PMID:9256433
          supporting_text: recombinant P-TEN dephosphorylated protein and 
            peptide substrates phosphorylated on serine, threonine, and tyrosine
            residues
  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate of IBA annotation for the same term. PTEN has 
        documented protein tyrosine phosphatase activity.
      action: ACCEPT
      reason: Consistent with experimental evidence for PTEN's dual-specificity 
        phosphatase activity.
  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: General phosphoprotein phosphatase activity term. PTEN does have 
        protein phosphatase activity but more specific terms (GO:0004722, 
        GO:0004725) are preferred.
      action: ACCEPT
      reason: Accurate but less specific than existing annotations. Still valid 
        as a parent term.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: PTEN-Long (PTEN-L/alpha) isoform can be secreted and taken up by 
        other cells. This applies specifically to the N-terminally extended 
        isoform.
      action: ACCEPT
      reason: The PTEN-L isoform has been shown to be secreted and function in 
        neighboring cells (PMID:23744781).
      supported_by:
        - reference_id: PMID:23744781
          supporting_text: A secreted PTEN phosphatase that enters cells to 
            alter signaling and survival
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Duplicate of IBA annotation. Nuclear localization of PTEN is 
        well-established.
      action: ACCEPT
      reason: Consistent with IBA annotation and extensive experimental evidence
        for nuclear PTEN.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PTEN is found in the cytoplasm. Cytosol (GO:0005829) is a more 
        specific term that is also annotated.
      action: ACCEPT
      reason: Cytoplasmic localization is accurate, though cytosol is the more 
        specific subcellular location.
  - term:
      id: GO:0006629
      label: lipid metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Very broad term. PTEN dephosphorylates phosphatidylinositols but 
        this is more accurately described as phosphatidylinositol 
        dephosphorylation (GO:0046856).
      action: MODIFY
      reason: Too general. GO:0046856 (phosphatidylinositol dephosphorylation) 
        is much more specific and accurate for PTEN's function.
      proposed_replacement_terms:
        - id: GO:0046856
          label: phosphatidylinositol dephosphorylation
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PTEN promotes apoptosis by inhibiting PI3K/AKT survival 
        signaling. This is a downstream effect of PTEN's lipid phosphatase 
        activity rather than a direct function.
      action: KEEP_AS_NON_CORE
      reason: Apoptosis regulation is a downstream consequence of PTEN's 
        inhibition of AKT survival signaling, not a direct molecular function.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: ectopic expression of the phosphatase in 
            PTEN-deficient tumor cell lines resulted in the inhibition of 
            protein kinase (PK) B/Akt and regulation of cell survival
  - term:
      id: GO:0007399
      label: nervous system development
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PTEN plays important roles in nervous system development by 
        regulating neuron size, dendritic arborization, and synapse formation 
        through PI3K/AKT/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: While PTEN has well-documented roles in nervous system development
        (PTEN mutations cause macrocephaly and autism spectrum disorders), this 
        is a pleiotropic effect of its core lipid phosphatase function.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PTEN suppresses cell proliferation through its antagonism of 
        PI3K/AKT/mTOR signaling. This is a key aspect of its tumor suppressor 
        function.
      action: KEEP_AS_NON_CORE
      reason: While this is a fundamental consequence of PTEN function and 
        central to its tumor suppressor role, it is a downstream effect of 
        PI3K/AKT pathway inhibition rather than a direct molecular function.
      supported_by:
        - reference_id: PMID:10468583
          supporting_text: The tumor-suppressor activity of PTEN is regulated by
            its carboxyl-terminal region
  - term:
      id: GO:0008289
      label: lipid binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PTEN binds phosphatidylinositol lipids as substrates via its C2 
        domain and phosphatase domain.
      action: ACCEPT
      reason: PTEN's C2 domain mediates membrane/lipid binding which is 
        essential for its localization and function.
  - term:
      id: GO:0009966
      label: regulation of signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Very broad term. PTEN specifically regulates PI3K/AKT signal 
        transduction via its lipid phosphatase activity.
      action: MODIFY
      reason: Too general. GO:0051898 (negative regulation of PI3K/AKT 
        signaling) is more specific and accurate.
      proposed_replacement_terms:
        - id: GO:0051898
          label: negative regulation of phosphatidylinositol 3-kinase/protein 
            kinase B signal transduction
  - term:
      id: GO:0010604
      label: positive regulation of macromolecule metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Very broad and vague term with unclear relationship to PTEN's 
        core functions. PTEN actually inhibits anabolic processes by suppressing
        mTOR signaling.
      action: REMOVE
      reason: This annotation is too vague and potentially misleading. PTEN 
        generally suppresses anabolic metabolism through mTOR inhibition rather 
        than promoting macromolecule metabolism.
  - term:
      id: GO:0010648
      label: negative regulation of cell communication
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Very broad term. PTEN specifically inhibits PI3K/AKT signaling.
      action: MODIFY
      reason: Too general. GO:0051898 (negative regulation of PI3K/AKT 
        signaling) is the specific pathway PTEN regulates.
      proposed_replacement_terms:
        - id: GO:0051898
          label: negative regulation of phosphatidylinositol 3-kinase/protein 
            kinase B signal transduction
  - term:
      id: GO:0016314
      label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate of IBA annotation. This is PTEN's primary enzymatic 
        activity.
      action: ACCEPT
      reason: Consistent with IBA annotation and extensive experimental 
        evidence. This is the core molecular function of PTEN.
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Very broad parent term for PTEN's phosphatase activities.
      action: ACCEPT
      reason: While very general, this is technically accurate as a parent term 
        of phosphatase activity.
  - term:
      id: GO:0016791
      label: phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: General phosphatase activity term. More specific terms for lipid 
        and protein phosphatase activities are preferred.
      action: ACCEPT
      reason: Accurate as a parent term, though more specific annotations exist.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PTEN binds multiple enzymes including kinases and ubiquitin 
        ligases that regulate its activity and stability.
      action: ACCEPT
      reason: PTEN interacts with various enzymes for regulation of its 
        activity, localization, and stability.
  - term:
      id: GO:0023057
      label: negative regulation of signaling
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Broad term. PTEN specifically negatively regulates PI3K/AKT 
        signaling.
      action: MODIFY
      reason: Too general. GO:0051898 (negative regulation of PI3K/AKT 
        signaling) is more specific.
      proposed_replacement_terms:
        - id: GO:0051898
          label: negative regulation of phosphatidylinositol 3-kinase/protein 
            kinase B signal transduction
  - term:
      id: GO:0030351
      label: inositol-1,3,4,5,6-pentakisphosphate 3-phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: PTEN can dephosphorylate soluble inositol phosphates in addition 
        to phosphatidylinositol lipids.
      action: ACCEPT
      reason: This activity has been demonstrated experimentally 
        (PMID:11418101).
      supported_by:
        - reference_id: PMID:11418101
          supporting_text: Expanding coincident signaling by PTEN through its 
            inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity
  - term:
      id: GO:0045595
      label: regulation of cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PTEN affects cell differentiation through PI3K/AKT/mTOR pathway 
        modulation.
      action: KEEP_AS_NON_CORE
      reason: This is a downstream pleiotropic effect of PTEN's lipid 
        phosphatase activity, not a core function.
  - term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Duplicate of IBA annotation. Core biological process for PTEN.
      action: ACCEPT
      reason: Consistent with IBA annotation. This is a core process term for 
        PTEN's primary function.
  - term:
      id: GO:0051093
      label: negative regulation of developmental process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Very broad term. PTEN affects development through PI3K/AKT 
        pathway regulation.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect of PTEN's lipid phosphatase 
        activity. Too general to be informative.
  - term:
      id: GO:0051129
      label: negative regulation of cellular component organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Very broad term with unclear mechanistic connection to PTEN's 
        core functions.
      action: MARK_AS_OVER_ANNOTATED
      reason: This is too vague and likely an over-annotation. PTEN's effects on
        cellular organization are indirect consequences of PI3K/AKT signaling 
        modulation.
  - term:
      id: GO:0051241
      label: negative regulation of multicellular organismal process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Very broad term with unclear mechanistic basis.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too vague to be informative. This is an indirect consequence of 
        PTEN's lipid phosphatase activity.
  - term:
      id: GO:0051717
      label: inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PTEN can dephosphorylate soluble inositol polyphosphates 
        including I(1,3,4,5)P4.
      action: ACCEPT
      reason: This activity has been demonstrated experimentally (PMID:9593664).
      supported_by:
        - reference_id: PMID:9593664
          supporting_text: The tumor suppressor, PTEN/MMAC1, dephosphorylates 
            the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
  - term:
      id: GO:0051726
      label: regulation of cell cycle
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PTEN regulates cell cycle through multiple mechanisms including 
        AKT-mediated effects on p27/p21 and nuclear PTEN effects on APC/CDH1.
      action: KEEP_AS_NON_CORE
      reason: While PTEN has well-documented effects on cell cycle, these are 
        downstream of its lipid phosphatase activity and nuclear functions, not 
        a primary molecular function.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner
  - term:
      id: GO:0051800
      label: phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: PTEN can dephosphorylate PI(3,4)P2 in addition to PIP3, though 
        PIP3 is the primary substrate.
      action: ACCEPT
      reason: This is a documented enzymatic activity of PTEN (PMID:9811831).
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: Characterization of the lipid phosphatase activity of
            PTEN demonstrates that it shows specificity for 
            phosphatidylinositols phosphorylated at the 3 position
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15951562
    review:
      summary: PTEN binds PDZ domain-containing proteins (MAGI2, MAGI3, MAST1, 
        MAST2, MAST3) through its C-terminal PDZ-binding motif.
      action: MODIFY
      reason: Generic protein binding is uninformative. GO:0030165 (PDZ domain 
        binding) is more specific and accurate for this interaction.
      proposed_replacement_terms:
        - id: GO:0030165
          label: PDZ domain binding
      supported_by:
        - reference_id: PMID:15951562
          supporting_text: Binding of PTEN to specific PDZ domains contributes 
            to PTEN protein stability and phosphorylation by 
            microtubule-associated serine/threonine kinases
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16456542
    review:
      summary: PTEN associates with NHERF proteins to attenuate PDGF receptor 
        signaling.
      action: MODIFY
      reason: Generic protein binding is uninformative. More specific term for 
        NHERF/PDZ scaffold binding is preferred.
      proposed_replacement_terms:
        - id: GO:0030165
          label: PDZ domain binding
      supported_by:
        - reference_id: PMID:16456542
          supporting_text: PTEN tumor suppressor associates with NHERF proteins 
            to attenuate PDGF receptor signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17274640
    review:
      summary: PTEN interacts with protein phosphatase 1.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative. More specific binding 
        terms should be used when the interacting partner is known.
      supported_by:
        - reference_id: PMID:17274640
          supporting_text: A limited screen for protein interactions reveals new
            roles for protein phosphatase 1 in cell cycle control and apoptosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19345329
    review:
      summary: PTEN interacts with FRK kinase which phosphorylates and 
        stabilizes PTEN.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative. The specific interaction
        with FRK kinase is relevant for PTEN regulation but would be better 
        annotated with a kinase binding term.
      supported_by:
        - reference_id: PMID:19345329
          supporting_text: Rak functions as a tumor suppressor by regulating 
            PTEN protein stability and function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19369943
    review:
      summary: PTEN interacts with peroxiredoxin 1 (Prdx1) which regulates PTEN 
        oxidation.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:19369943
          supporting_text: Prdx1 inhibits tumorigenesis via regulating PTEN/AKT 
            activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19903340
    review:
      summary: PTEN inhibits BMI1 function independently of its phosphatase 
        activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative. This interaction 
        represents a non-canonical PTEN function.
      supported_by:
        - reference_id: PMID:19903340
          supporting_text: PTEN inhibits BMI1 function independently of its 
            phosphatase activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN interacts with the APC-CDH1 complex.
      action: MODIFY
      reason: More specific term should be used. GO:0010997 (anaphase-promoting 
        complex binding) is appropriate.
      proposed_replacement_terms:
        - id: GO:0010997
          label: anaphase-promoting complex binding
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21653829
    review:
      summary: High-throughput study of protein interactions in autism spectrum 
        disorders.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding from high-throughput study is 
        uninformative without specific interactor information.
      supported_by:
        - reference_id: PMID:21653829
          supporting_text: Protein interactome reveals converging molecular 
            pathways among autism disorders.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21804599
    review:
      summary: PTEN forms a tumor suppressor network with NHERF1 and PHLPP.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative. Specific 
        scaffold/adapter binding terms would be more appropriate.
      supported_by:
        - reference_id: PMID:21804599
          supporting_text: PTEN, NHERF1 and PHLPP form a tumor suppressor 
            network that is disabled in glioblastoma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23514585
    review:
      summary: PTEN suppresses oncogenic AIB1 by promoting its degradation via 
        Fbw7.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:23514585
          supporting_text: PTEN suppresses the oncogenic function of AIB1 
            through decreasing its protein stability via mechanism involving 
            Fbw7 alpha.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23940795
    review:
      summary: PTEN interacts with drebrin and regulates its phosphorylation.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:23940795
          supporting_text: Phosphorylation of the actin binding protein Drebrin 
            at S647 is regulated by neuronal activity and PTEN.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24012959
    review:
      summary: PTEN interacts with NHERF1 which regulates PDGF receptor 
        signaling.
      action: MODIFY
      reason: Generic protein binding is uninformative. GO:0030165 (PDZ domain 
        binding) is more specific.
      proposed_replacement_terms:
        - id: GO:0030165
          label: PDZ domain binding
      supported_by:
        - reference_id: PMID:24012959
          supporting_text: Epub 2013 Sep 5. Breast cancer-derived K172N, D301V 
            mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of
            platelet-derived growth factor receptor signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24656772
    review:
      summary: PTEN is a substrate of SPOP ubiquitin ligase.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative. This represents PTEN 
        regulation by ubiquitination.
      supported_by:
        - reference_id: PMID:24656772
          supporting_text: 2014 Mar 20. SPOP promotes tumorigenesis by acting as
            a key regulatory hub in kidney cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: High-throughput proximity ligation assay study.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding from high-throughput study is 
        uninformative.
      supported_by:
        - reference_id: PMID:25241761
          supporting_text: Oct 9. Using an in situ proximity ligation assay to 
            systematically profile endogenous protein-protein interactions in a 
            pathway network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:36950384
    review:
      summary: Protein interaction study in neurons related to autism.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding from high-throughput study is 
        uninformative.
      supported_by:
        - reference_id: PMID:36950384
          supporting_text: eCollection 2023 Mar 8.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:24766807
    review:
      summary: Cancer-associated PTEN mutants can act in a dominant-negative 
        manner by binding to wild-type PTEN, suggesting PTEN dimerization.
      action: ACCEPT
      reason: PTEN homodimerization is documented and may be relevant for its 
        regulation and for dominant-negative effects of cancer mutations.
      supported_by:
        - reference_id: PMID:24766807
          supporting_text: Cancer-associated PTEN mutants act in a 
            dominant-negative manner to suppress PTEN protein function
  - term:
      id: GO:0006661
      label: phosphatidylinositol biosynthetic process
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1660499
    review:
      summary: PTEN is involved in phosphatidylinositol metabolism by 
        dephosphorylating 3-phosphorylated phosphoinositides, but this is 
        catabolism not biosynthesis.
      action: MODIFY
      reason: PTEN dephosphorylates phosphoinositides (catabolic), not 
        biosynthesis. GO:0046856 (phosphatidylinositol dephosphorylation) is 
        more accurate.
      proposed_replacement_terms:
        - id: GO:0046856
          label: phosphatidylinositol dephosphorylation
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199456
    review:
      summary: PTEN negatively regulates PI3K/AKT signaling by dephosphorylating
        PIP3. This is a core process annotation.
      action: ACCEPT
      reason: This is the primary biological process in which PTEN functions. 
        Core annotation.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: PTEN functions to suppress these growth-promoting and
            survival signals by dephosphorylating the phospholipid products of 
            PI 3-kinase
  - term:
      id: GO:0016314
      label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199456
    review:
      summary: PTEN's primary enzymatic activity. Duplicate of IBA and IDA 
        annotations.
      action: ACCEPT
      reason: Core molecular function of PTEN. Essential for tumor suppression.
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IPI
    original_reference_id: PMID:20123964
    review:
      summary: PTEN can interact with beta-catenin, potentially regulating Wnt 
        signaling.
      action: UNDECIDED
      reason: The reference PMID:20123964 is about lipid phosphate phosphatase 3
        (LPP3), not PTEN directly. Need to verify if this annotation is 
        correctly assigned.
      supported_by:
        - reference_id: PMID:20123964
          supporting_text: Feb 1. Lipid phosphate phosphatase 3 stabilization of
            beta-catenin induces endothelial cell migration and formation of 
            branching point structures.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20123964
    review:
      summary: This annotation appears to be from a study on LPP3, not PTEN 
        directly.
      action: UNDECIDED
      reason: Need to verify reference relevance. PMID:20123964 title is about 
        LPP3, not PTEN.
      supported_by:
        - reference_id: PMID:20123964
          supporting_text: Feb 1. Lipid phosphate phosphatase 3 stabilization of
            beta-catenin induces endothelial cell migration and formation of 
            branching point structures.
  - term:
      id: GO:0051800
      label: phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:20123964
    review:
      summary: PI(3,4)P2 3-phosphatase activity is documented for PTEN, but this
        reference appears to be about LPP3.
      action: ACCEPT
      reason: This activity is well-documented for PTEN (PMID:9811831), though 
        the reference may need correction.
      supported_by:
        - reference_id: PMID:20123964
          supporting_text: Feb 1. Lipid phosphate phosphatase 3 stabilization of
            beta-catenin induces endothelial cell migration and formation of 
            branching point structures.
  - term:
      id: GO:1902533
      label: positive regulation of intracellular signal transduction
    evidence_type: IMP
    original_reference_id: PMID:20123964
    review:
      summary: This annotation appears misattributed. PTEN generally negatively 
        regulates signaling.
      action: UNDECIDED
      reason: PTEN typically inhibits signaling via PI3K/AKT pathway. This 
        positive regulation annotation may be incorrectly assigned or 
        context-specific.
      supported_by:
        - reference_id: PMID:20123964
          supporting_text: Feb 1. Lipid phosphate phosphatase 3 stabilization of
            beta-catenin induces endothelial cell migration and formation of 
            branching point structures.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: PTEN localizes to the nucleoplasm where it has 
        phosphatase-independent functions in genomic stability and chromatin 
        regulation.
      action: ACCEPT
      reason: Nuclear PTEN is well-documented with important functions including
        interaction with APC-CDH1 and regulation of genomic stability.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: PTEN is present in the cytosol where it can function as both 
        lipid and protein phosphatase
      action: ACCEPT
      reason: Cytosolic localization allows PTEN to regulate multiple signaling 
        pathways beyond membrane-associated functions
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:10760291
    review:
      summary: PTEN localizes to the plasma membrane where it dephosphorylates 
        PIP3 to antagonize PI3K signaling
      action: ACCEPT
      reason: Plasma membrane localization is essential for PTEN's core lipid 
        phosphatase function against PIP3
      supported_by:
        - reference_id: PMID:10760291
          supporting_text: Evidence for regulation of the PTEN tumor suppressor 
            by a membrane-localized multi-PDZ domain containing scaffold protein
            MAGI-2.
  - term:
      id: GO:0030351
      label: inositol-1,3,4,5,6-pentakisphosphate 3-phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:11418101
    review:
      summary: PTEN can dephosphorylate soluble inositol polyphosphates. This is
        a secondary enzymatic activity.
      action: ACCEPT
      reason: This activity is documented experimentally in the cited reference.
      supported_by:
        - reference_id: PMID:11418101
          supporting_text: Expanding coincident signaling by PTEN through its 
            inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity
  - term:
      id: GO:0045668
      label: negative regulation of osteoblast differentiation
    evidence_type: IDA
    original_reference_id: PMID:22869525
    review:
      summary: PTEN regulates osteoblast differentiation through PI3K/AKT 
        pathway modulation.
      action: KEEP_AS_NON_CORE
      reason: This is a tissue-specific downstream effect of PTEN's lipid 
        phosphatase activity, not a core function.
      supported_by:
        - reference_id: PMID:22869525
          supporting_text: Aug 6. Insulin-like growth factor (IGF) binding 
            protein 2 functions coordinately with receptor protein tyrosine 
            phosphatase β and the IGF-I receptor to regulate IGF-I-stimulated 
            signaling.
  - term:
      id: GO:0051800
      label: phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1676149
    review:
      summary: PI(3,4)P2 3-phosphatase activity is documented for PTEN. 
        Duplicate of IEA annotation.
      action: ACCEPT
      reason: This is a documented enzymatic activity of PTEN (PMID:9811831).
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Core process annotation for PTEN. Duplicate of TAS/IDA 
        annotations.
      action: ACCEPT
      reason: This is the primary biological process in which PTEN functions.
  - term:
      id: GO:0007270
      label: neuron-neuron synaptic transmission
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects synaptic transmission through PI3K/AKT pathway 
        modulation in neurons.
      action: KEEP_AS_NON_CORE
      reason: Downstream tissue-specific effect. PTEN mutations cause 
        neurological phenotypes including autism spectrum disorders.
  - term:
      id: GO:0007611
      label: learning or memory
    evidence_type: ISS
    original_reference_id: PMID:16675393
    review:
      summary: PTEN deletion in mouse neurons affects learning and memory 
        through PI3K/mTOR pathway dysregulation.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect based on mouse studies. Not a core 
        molecular function.
      supported_by:
        - reference_id: PMID:16675393
          supporting_text: Pten regulates neuronal arborization and social 
            interaction in mice.
  - term:
      id: GO:0007626
      label: locomotory behavior
    evidence_type: ISS
    original_reference_id: PMID:16675393
    review:
      summary: Neuronal PTEN deletion affects locomotory behavior in mouse 
        studies.
      action: KEEP_AS_NON_CORE
      reason: Downstream behavioral effect. Very distant from PTEN's core lipid 
        phosphatase function.
      supported_by:
        - reference_id: PMID:16675393
          supporting_text: Pten regulates neuronal arborization and social 
            interaction in mice.
  - term:
      id: GO:0021542
      label: dentate gyrus development
    evidence_type: ISS
    original_reference_id: PMID:17706614
    review:
      summary: PTEN regulates dentate gyrus development via PI3K/AKT pathway.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental effect. Not a core function.
      supported_by:
        - reference_id: PMID:17706614
          supporting_text: 2007 Jul 20. A seizure-prone phenotype is associated 
            with altered free-running rhythm in Pten mutant mice.
  - term:
      id: GO:0021955
      label: central nervous system neuron axonogenesis
    evidence_type: ISS
    original_reference_id: PMID:16675393
    review:
      summary: PTEN regulates axon growth through PI3K/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect on neuronal development. Not a core function.
      supported_by:
        - reference_id: PMID:16675393
          supporting_text: Pten regulates neuronal arborization and social 
            interaction in mice.
  - term:
      id: GO:0030534
      label: adult behavior
    evidence_type: ISS
    original_reference_id: PMID:16675393
    review:
      summary: PTEN affects adult behavior through neuronal PI3K/AKT signaling.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too vague and distant from core molecular function. 
        Over-annotation.
      supported_by:
        - reference_id: PMID:16675393
          supporting_text: Pten regulates neuronal arborization and social 
            interaction in mice.
  - term:
      id: GO:0032286
      label: central nervous system myelin maintenance
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects myelination through PI3K/AKT/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific effect. Not a core function.
  - term:
      id: GO:0035176
      label: social behavior
    evidence_type: ISS
    original_reference_id: PMID:16675393
    review:
      summary: PTEN deletion in neurons affects social behavior (autism-like 
        phenotypes).
      action: MARK_AS_OVER_ANNOTATED
      reason: Behavioral phenotype very distant from core molecular function.
      supported_by:
        - reference_id: PMID:16675393
          supporting_text: Pten regulates neuronal arborization and social 
            interaction in mice.
  - term:
      id: GO:0042711
      label: maternal behavior
    evidence_type: ISS
    original_reference_id: PMID:16675393
    review:
      summary: PTEN affects maternal behavior through neuronal functions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Behavioral phenotype very distant from core molecular function.
      supported_by:
        - reference_id: PMID:16675393
          supporting_text: Pten regulates neuronal arborization and social 
            interaction in mice.
  - term:
      id: GO:0043005
      label: neuron projection
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN localizes to and regulates neuron projections.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific localization. Valid but not a core function.
  - term:
      id: GO:0045475
      label: locomotor rhythm
    evidence_type: ISS
    original_reference_id: PMID:17706614
    review:
      summary: PTEN affects locomotor rhythms through circadian/neuronal 
        mechanisms.
      action: MARK_AS_OVER_ANNOTATED
      reason: Very indirect behavioral effect.
      supported_by:
        - reference_id: PMID:17706614
          supporting_text: 2007 Jul 20. A seizure-prone phenotype is associated 
            with altered free-running rhythm in Pten mutant mice.
  - term:
      id: GO:0045792
      label: negative regulation of cell size
    evidence_type: ISS
    original_reference_id: PMID:21411674
    review:
      summary: PTEN suppresses cell growth/size through PI3K/mTOR inhibition.
      action: KEEP_AS_NON_CORE
      reason: Well-documented downstream effect but not a core molecular 
        function.
      supported_by:
        - reference_id: PMID:21411674
          supporting_text: Pten knockdown in vivo increases excitatory drive 
            onto dentate granule cells.
  - term:
      id: GO:0046621
      label: negative regulation of organ growth
    evidence_type: ISS
    original_reference_id: PMID:19208814
    review:
      summary: PTEN suppresses organ growth via PI3K/AKT/mTOR pathway 
        inhibition.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect.
      supported_by:
        - reference_id: PMID:19208814
          supporting_text: Haploinsufficiency for Pten and Serotonin transporter
            cooperatively influences brain size and social behavior.
  - term:
      id: GO:0060024
      label: rhythmic synaptic transmission
    evidence_type: ISS
    original_reference_id: PMID:17706614
    review:
      summary: PTEN affects rhythmic synaptic transmission in circadian 
        circuits.
      action: MARK_AS_OVER_ANNOTATED
      reason: Very specialized neuronal function.
      supported_by:
        - reference_id: PMID:17706614
          supporting_text: 2007 Jul 20. A seizure-prone phenotype is associated 
            with altered free-running rhythm in Pten mutant mice.
  - term:
      id: GO:0060074
      label: synapse maturation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN regulates synapse maturation through PI3K/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific developmental effect.
  - term:
      id: GO:0060134
      label: prepulse inhibition
    evidence_type: ISS
    original_reference_id: PMID:19208814
    review:
      summary: PTEN affects sensorimotor gating (prepulse inhibition).
      action: MARK_AS_OVER_ANNOTATED
      reason: Very specialized behavioral/neurological phenotype.
      supported_by:
        - reference_id: PMID:19208814
          supporting_text: Haploinsufficiency for Pten and Serotonin transporter
            cooperatively influences brain size and social behavior.
  - term:
      id: GO:0060997
      label: dendritic spine morphogenesis
    evidence_type: ISS
    original_reference_id: PMID:18082964
    review:
      summary: PTEN regulates dendritic spine morphology through PI3K/mTOR 
        signaling.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific structural effect.
      supported_by:
        - reference_id: PMID:18082964
          supporting_text: Phosphatase and tensin homolog, deleted on chromosome
            10 deficiency in brain causes defects in synaptic structure, 
            transmission and plasticity, and myelination abnormalities.
  - term:
      id: GO:0090394
      label: negative regulation of excitatory postsynaptic potential
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects synaptic transmission.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific effect.
  - term:
      id: GO:0097105
      label: presynaptic membrane assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects presynaptic structure.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific structural effect.
  - term:
      id: GO:0097107
      label: postsynaptic density assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects postsynaptic structure via PI3K/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific structural effect.
  - term:
      id: GO:1990757
      label: ubiquitin ligase activator activity
    evidence_type: ISS
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN activates APC-CDH1 E3 ubiquitin ligase in a 
        phosphatase-independent manner.
      action: ACCEPT
      reason: This represents a non-canonical function of nuclear PTEN that is 
        independent of its phosphatase activity but important for tumor 
        suppression.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner
  - term:
      id: GO:2000463
      label: positive regulation of excitatory postsynaptic potential
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects synaptic transmission.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific effect. Note this conflicts with GO:0090394 
        (negative regulation) which may indicate context-dependency.
  - term:
      id: GO:2000808
      label: negative regulation of synaptic vesicle clustering
    evidence_type: ISS
    original_reference_id: PMID:18082964
    review:
      summary: PTEN affects synaptic vesicle organization.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific structural effect.
      supported_by:
        - reference_id: PMID:18082964
          supporting_text: Phosphatase and tensin homolog, deleted on chromosome
            10 deficiency in brain causes defects in synaptic structure, 
            transmission and plasticity, and myelination abnormalities.
  - term:
      id: GO:0007056
      label: spindle assembly involved in female meiosis
    evidence_type: IDA
    original_reference_id: PMID:31492966
    review:
      summary: PTEN degradation is required for oocyte meiotic resumption. PTEN 
        affects spindle assembly during oocyte meiosis.
      action: KEEP_AS_NON_CORE
      reason: Specialized cell type-specific role in meiosis. Not a core 
        molecular function.
      supported_by:
        - reference_id: PMID:31492966
          supporting_text: Epub 2019 Sep 6. The CRL4-DCAF13 ubiquitin E3 ligase 
            supports oocyte meiotic resumption by targeting PTEN degradation.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IDA
    original_reference_id: PMID:31492966
    review:
      summary: Core process annotation. PTEN negatively regulates PI3K/AKT 
        signaling in oocytes.
      action: ACCEPT
      reason: Duplicate of TAS/ISS annotations. Core function.
      supported_by:
        - reference_id: PMID:31492966
          supporting_text: Epub 2019 Sep 6. The CRL4-DCAF13 ubiquitin E3 ligase 
            supports oocyte meiotic resumption by targeting PTEN degradation.
  - term:
      id: GO:0052866
      label: phosphatidylinositol phosphate phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9811831
    review:
      summary: General phosphatidylinositol phosphate phosphatase activity. The 
        more specific GO:0016314 (PIP3 3-phosphatase) is preferred.
      action: ACCEPT
      reason: Accurate parent term for PTEN's lipid phosphatase activities.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: Characterization of the lipid phosphatase activity of
            PTEN demonstrates that it shows specificity for 
            phosphatidylinositols phosphorylated at the 3 position
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5689950
    review:
      summary: Duplicate nucleoplasm annotation. PTEN localizes to nucleoplasm.
      action: ACCEPT
      reason: Nuclear PTEN localization is well-established.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807118
    review:
      summary: Duplicate nucleoplasm annotation.
      action: ACCEPT
      reason: Consistent with other nucleoplasm annotations.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807126
    review:
      summary: Duplicate nucleoplasm annotation.
      action: ACCEPT
      reason: Consistent with other nucleoplasm annotations.
  - term:
      id: GO:2000773
      label: negative regulation of cellular senescence
    evidence_type: ISS
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN affects cellular senescence through APC-CDH1 complex
        regulation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's nuclear functions.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:0033137
      label: negative regulation of peptidyl-serine phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:10918569
    review:
      summary: PTEN inhibits AKT-mediated serine phosphorylation of downstream 
        targets by reducing PIP3 levels.
      action: KEEP_AS_NON_CORE
      reason: This is an indirect consequence of PTEN's inhibition of AKT 
        signaling.
      supported_by:
        - reference_id: PMID:10918569
          supporting_text: 'PTEN expression is reduced in a subset of sporadic thyroid
            carcinomas: evidence that PTEN-growth suppressing activity in thyroid
            cancer cells mediated by p27kip1.'
  - term:
      id: GO:1902807
      label: negative regulation of cell cycle G1/S phase transition
    evidence_type: IDA
    original_reference_id: PMID:10918569
    review:
      summary: PTEN inhibits G1/S transition through AKT-mediated effects on 
        cell cycle regulators like p27.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PI3K/AKT pathway inhibition.
      supported_by:
        - reference_id: PMID:10918569
          supporting_text: 'PTEN expression is reduced in a subset of sporadic thyroid
            carcinomas: evidence that PTEN-growth suppressing activity in thyroid
            cancer cells mediated by p27kip1.'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2317387
    review:
      summary: Duplicate cytosol annotation.
      action: ACCEPT
      reason: Consistent with IBA and IDA cytosol annotations.
  - term:
      id: GO:0010977
      label: negative regulation of neuron projection development
    evidence_type: ISS
    original_reference_id: PMID:28008308
    review:
      summary: PTEN negatively regulates neuron projection development through 
        PI3K/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific downstream effect.
      supported_by:
        - reference_id: PMID:28008308
          supporting_text: eCollection 2016. The Protective Role of 
            microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta 
            Amyloid-Triggered Endoplasmic Reticulum Stress.
  - term:
      id: GO:1904706
      label: negative regulation of vascular associated smooth muscle cell 
        proliferation
    evidence_type: IMP
    original_reference_id: PMID:26208095
    review:
      summary: PTEN suppresses vascular smooth muscle cell proliferation through
        PI3K/AKT pathway inhibition.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific downstream effect of PTEN's core lipid 
        phosphatase function.
      supported_by:
        - reference_id: PMID:26208095
          supporting_text: eCollection 2015. PPARγ Ligands Attenuate 
            Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth 
            Muscle Cells through Modulation of MicroRNA-21.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15355975
    review:
      summary: PTEN interacts with NOP53 which regulates PTEN stability.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:15355975
          supporting_text: 2004 Sep 7. Regulation of PTEN phosphorylation and 
            stability by a tumor suppressor candidate protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25007873
    review:
      summary: PTEN interacts with PPP1R16B (TIMAP) in endothelial cells.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:25007873
          supporting_text: TIMAP promotes angiogenesis by suppressing 
            PTEN-mediated Akt inhibition in human glomerular endothelial cells.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: NAS
    original_reference_id: PMID:16762633
    review:
      summary: Core process annotation. Duplicate of IDA/TAS/ISS annotations.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:16762633
          supporting_text: Involvement of human micro-RNA in growth and response
            to chemotherapy in human cholangiocarcinoma cell lines.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:22879939
    review:
      summary: Core process annotation. Duplicate.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:22879939
          supporting_text: TGFβ-stimulated microRNA-21 utilizes PTEN to 
            orchestrate AKT/mTORC1 signaling for mesangial cell hypertrophy and 
            matrix expansion.
  - term:
      id: GO:0010719
      label: negative regulation of epithelial to mesenchymal transition
    evidence_type: IMP
    original_reference_id: PMID:27919618
    review:
      summary: PTEN suppresses EMT through PI3K/AKT pathway inhibition.
      action: KEEP_AS_NON_CORE
      reason: Downstream process related to PTEN's tumor suppressor function.
      supported_by:
        - reference_id: PMID:27919618
          supporting_text: Epub 2016 Nov 18. Electric field-induced suppression 
            of PTEN drives epithelial-to-mesenchymal transition via mTORC1 
            activation.
  - term:
      id: GO:0051548
      label: negative regulation of keratinocyte migration
    evidence_type: IMP
    original_reference_id: PMID:27919618
    review:
      summary: PTEN inhibits keratinocyte migration through PI3K/AKT signaling.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific migration effect.
      supported_by:
        - reference_id: PMID:27919618
          supporting_text: Epub 2016 Nov 18. Electric field-induced suppression 
            of PTEN drives epithelial-to-mesenchymal transition via mTORC1 
            activation.
  - term:
      id: GO:0071257
      label: cellular response to electrical stimulus
    evidence_type: IMP
    original_reference_id: PMID:27919618
    review:
      summary: PTEN affects cellular responses to electrical stimulation in 
        wound healing contexts.
      action: MARK_AS_OVER_ANNOTATED
      reason: Very specialized experimental context. Distant from core function.
      supported_by:
        - reference_id: PMID:27919618
          supporting_text: Epub 2016 Nov 18. Electric field-induced suppression 
            of PTEN drives epithelial-to-mesenchymal transition via mTORC1 
            activation.
  - term:
      id: GO:1903690
      label: negative regulation of wound healing, spreading of epidermal cells
    evidence_type: IMP
    original_reference_id: PMID:27919618
    review:
      summary: PTEN inhibits epidermal cell spreading during wound healing.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific effect related to PTEN's effects on cell motility.
      supported_by:
        - reference_id: PMID:27919618
          supporting_text: Epub 2016 Nov 18. Electric field-induced suppression 
            of PTEN drives epithelial-to-mesenchymal transition via mTORC1 
            activation.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:26280536
    review:
      summary: Core process annotation. Duplicate.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:26280536
          supporting_text: Deubiquitylase OTUD3 regulates PTEN stability and 
            suppresses tumorigenesis.
  - term:
      id: GO:1990381
      label: ubiquitin-specific protease binding
    evidence_type: IPI
    original_reference_id: PMID:26280536
    review:
      summary: PTEN binds USP13 which deubiquitinates and stabilizes PTEN.
      action: ACCEPT
      reason: This is a specific binding activity relevant to PTEN regulation. 
        More informative than generic protein binding.
      supported_by:
        - reference_id: PMID:26280536
          supporting_text: Deubiquitylase OTUD3 regulates PTEN stability and 
            suppresses tumorigenesis.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1676149
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Cytosolic localization is well-established for PTEN.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1855205
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199456
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2321904
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807106
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807126
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807134
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807206
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8847968
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8847977
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8850945
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8850961
    review:
      summary: Duplicate cytosol annotation from Reactome.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0030336
      label: negative regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:21573166
    review:
      summary: PTEN inhibits cell migration through PI3K/AKT pathway inhibition.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's lipid phosphatase activity. 
        Well-documented but not a core molecular function.
      supported_by:
        - reference_id: PMID:9616126
          supporting_text: Inhibition of cell migration, spreading, and focal 
            adhesions by tumor suppressor PTEN
        - reference_id: PMID:21573166
          supporting_text: Upregulated microRNA-29a by hepatitis B virus X 
            protein enhances hepatoma cell migration by targeting PTEN in cell 
            culture model.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:21573166
    review:
      summary: Core process annotation. Duplicate.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:21573166
          supporting_text: Upregulated microRNA-29a by hepatitis B virus X 
            protein enhances hepatoma cell migration by targeting PTEN in cell 
            culture model.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807105
    review:
      summary: Duplicate nucleoplasm annotation.
      action: ACCEPT
      reason: Consistent with other nucleoplasm annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6807105
    review:
      summary: Duplicate cytosol annotation.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:24862762
    review:
      summary: PTEN nuclear localization is important for its protein 
        phosphatase functions and genomic stability
      action: ACCEPT
      reason: Nuclear localization enables PTEN's protein phosphatase activity 
        and non-canonical tumor suppressor functions
      supported_by:
        - reference_id: PMID:24862762
          supporting_text: NHERF1/EBP50 controls morphogenesis of 3D colonic 
            glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the 
            apical membrane.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:24862762
    review:
      summary: Duplicate cytoplasm annotation.
      action: ACCEPT
      reason: Cytoplasmic localization is well-established for PTEN.
      supported_by:
        - reference_id: PMID:24862762
          supporting_text: NHERF1/EBP50 controls morphogenesis of 3D colonic 
            glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the 
            apical membrane.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN generally negatively regulates cell proliferation. Positive 
        regulation may be context-specific.
      action: UNDECIDED
      reason: This contradicts PTEN's well-established role as an inhibitor of 
        cell proliferation. May be context-specific or incorrectly assigned.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: TAS
    original_reference_id: PMID:18082964
    review:
      summary: Core process annotation. Duplicate.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:18082964
          supporting_text: Phosphatase and tensin homolog, deleted on chromosome
            10 deficiency in brain causes defects in synaptic structure, 
            transmission and plasticity, and myelination abnormalities.
  - term:
      id: GO:0007416
      label: synapse assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN regulates synapse assembly through PI3K/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific developmental effect.
  - term:
      id: GO:0033555
      label: multicellular organismal response to stress
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Very broad term with unclear mechanistic basis.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too vague to be informative.
  - term:
      id: GO:0048853
      label: forebrain morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects forebrain development through PI3K/mTOR signaling 
        regulation of cell growth.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental effect.
  - term:
      id: GO:0050771
      label: negative regulation of axonogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN inhibits axon growth through PI3K/mTOR pathway.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific effect.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19473982
    review:
      summary: PTEN interacts with XIAP which ubiquitinates PTEN.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:19473982
          supporting_text: 2009 May 27. X-linked inhibitor of apoptosis protein 
            (XIAP) regulates PTEN ubiquitination, content, and 
            compartmentalization.
  - term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    evidence_type: IMP
    original_reference_id: PMID:21828076
    review:
      summary: Core process annotation. PTEN dephosphorylates 
        phosphatidylinositols.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:21828076
          supporting_text: 'Aug 9. A comprehensive functional analysis of PTEN mutations:
            implications in tumor- and autism-related syndromes.'
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:17880912
    review:
      summary: PTEN suppresses cell proliferation through PI3K/AKT pathway 
        inhibition.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's core lipid phosphatase activity.
      supported_by:
        - reference_id: PMID:17880912
          supporting_text: Epub 2007 Aug 22. MAGI-2 Inhibits cell migration and 
            proliferation via PTEN in human hepatocarcinoma cells.
  - term:
      id: GO:0030336
      label: negative regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:17880912
    review:
      summary: PTEN inhibits cell migration. Duplicate annotation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's lipid phosphatase activity.
      supported_by:
        - reference_id: PMID:17880912
          supporting_text: Epub 2007 Aug 22. MAGI-2 Inhibits cell migration and 
            proliferation via PTEN in human hepatocarcinoma cells.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:10760291
    review:
      summary: Duplicate cytoplasm annotation.
      action: ACCEPT
      reason: Consistent with other cytoplasm annotations.
      supported_by:
        - reference_id: PMID:10760291
          supporting_text: Evidence for regulation of the PTEN tumor suppressor 
            by a membrane-localized multi-PDZ domain containing scaffold protein
            MAGI-2.
  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:21241890
    review:
      summary: PTEN has phosphoprotein phosphatase activity in the nucleus.
      action: ACCEPT
      reason: This protein phosphatase activity has been demonstrated 
        experimentally.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN localization for APC-CDH1 regulation.
      action: ACCEPT
      reason: Well-documented nuclear localization with specific function.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:21241890
    review:
      summary: Duplicate cytoplasm annotation.
      action: ACCEPT
      reason: Consistent with other cytoplasm annotations.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:0010997
      label: anaphase-promoting complex binding
    evidence_type: IPI
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN binds the APC-CDH1 complex to activate its E3 ligase
        activity.
      action: ACCEPT
      reason: This represents an important phosphatase-independent function of 
        nuclear PTEN.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner
  - term:
      id: GO:2000060
      label: positive regulation of ubiquitin-dependent protein catabolic 
        process
    evidence_type: IDA
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN activates APC-CDH1 to promote ubiquitin-dependent 
        degradation of its substrates.
      action: KEEP_AS_NON_CORE
      reason: This is a downstream effect of PTEN's interaction with APC-CDH1, 
        not a core function.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:2000134
      label: negative regulation of G1/S transition of mitotic cell cycle
    evidence_type: IDA
    original_reference_id: PMID:21241890
    review:
      summary: Nuclear PTEN suppresses G1/S transition through APC-CDH1 
        activation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's nuclear APC-CDH1 activating function.
      supported_by:
        - reference_id: PMID:21241890
          supporting_text: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive
            complex in a phosphatase-independent manner.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17242191
    review:
      summary: PTEN interacts with DJ-1 which affects PTEN function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:17242191
          supporting_text: Jan 22. NHERF1/EBP50 head-to-tail intramolecular 
            interaction masks association with PDZ domain ligands.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:19057511
    review:
      summary: PTEN suppresses cell proliferation. Duplicate annotation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's lipid phosphatase activity.
      supported_by:
        - reference_id: PMID:19057511
          supporting_text: PTEN regulation by Akt-EGR1-ARF-PTEN axis.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:10940933
    review:
      summary: Duplicate cytoplasm annotation.
      action: ACCEPT
      reason: Consistent with other cytoplasm annotations.
      supported_by:
        - reference_id: PMID:10940933
          supporting_text: Subcellular localization of intracellular protein 
            tyrosine phosphatases in T cells.
  - term:
      id: GO:0050821
      label: protein stabilization
    evidence_type: IDA
    original_reference_id: PMID:20123964
    review:
      summary: This annotation appears to be from a study on LPP3, not PTEN.
      action: UNDECIDED
      reason: Need to verify reference relevance. PMID:20123964 is about LPP3.
      supported_by:
        - reference_id: PMID:20123964
          supporting_text: Feb 1. Lipid phosphate phosphatase 3 stabilization of
            beta-catenin induces endothelial cell migration and formation of 
            branching point structures.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:16845383
    review:
      summary: PTEN interacts with NDR kinases.
      action: ACCEPT
      reason: More informative than generic protein binding.
      supported_by:
        - reference_id: PMID:16845383
          supporting_text: Critical role for Daxx in regulating Mdm2.
  - term:
      id: GO:0010975
      label: regulation of neuron projection development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN regulates neuron projection development through PI3K/mTOR 
        signaling.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific effect.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17218261
    review:
      summary: Nuclear localization of PTEN regulated by ubiquitination.
      action: ACCEPT
      reason: Consistent with other nuclear PTEN annotations.
      supported_by:
        - reference_id: PMID:17218261
          supporting_text: Ubiquitination regulates PTEN nuclear import and 
            tumor suppression
  - term:
      id: GO:0051800
      label: phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9811831
    review:
      summary: PTEN can dephosphorylate PI(3,4)P2 at the D3 position.
      action: ACCEPT
      reason: Documented enzymatic activity.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: Characterization of the lipid phosphatase activity of
            PTEN demonstrates that it shows specificity for 
            phosphatidylinositols phosphorylated at the 3 position
  - term:
      id: GO:0051895
      label: negative regulation of focal adhesion assembly
    evidence_type: IMP
    original_reference_id: PMID:9616126
    review:
      summary: PTEN inhibits focal adhesion formation through PI3K/AKT pathway 
        modulation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect related to PTEN's effects on cell motility.
      supported_by:
        - reference_id: PMID:9616126
          supporting_text: Inhibition of cell migration, spreading, and focal 
            adhesions by tumor suppressor PTEN
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:10760291
    review:
      summary: Core process annotation. PTEN suppresses AKT activation.
      action: ACCEPT
      reason: Core biological process for PTEN.
      supported_by:
        - reference_id: PMID:10760291
          supporting_text: MAGI-2 enhances the ability of PTEN to suppress Akt 
            activation
  - term:
      id: GO:0004438
      label: phosphatidylinositol-3-phosphate phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9811831
    review:
      summary: PTEN can dephosphorylate PI(3)P. Secondary substrate.
      action: ACCEPT
      reason: Documented activity, though PIP3 is the primary substrate.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: The lipid phosphatase activity of PTEN is critical 
            for its tumor supressor function.
  - term:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9256433
    review:
      summary: PTEN has dual-specificity protein phosphatase activity including 
        serine/threonine.
      action: ACCEPT
      reason: Core molecular function documented in the seminal paper.
      supported_by:
        - reference_id: PMID:9256433
          supporting_text: recombinant P-TEN dephosphorylated protein and 
            peptide substrates phosphorylated on serine, threonine, and tyrosine
            residues, indicating that P-TEN is a dual-specificity phosphatase
  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9256433
    review:
      summary: PTEN has protein tyrosine phosphatase activity.
      action: ACCEPT
      reason: Core molecular function documented experimentally.
      supported_by:
        - reference_id: PMID:9256433
          supporting_text: recombinant P-TEN dephosphorylated protein and 
            peptide substrates phosphorylated on serine, threonine, and tyrosine
            residues
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:9187108
    review:
      summary: Early documentation of PTEN cytoplasmic localization.
      action: ACCEPT
      reason: Consistent with other cytoplasm annotations.
      supported_by:
        - reference_id: PMID:9187108
          supporting_text: TEP1, encoded by a candidate tumor suppressor locus, 
            is a novel protein tyrosine phosphatase regulated by transforming 
            growth factor beta.
  - term:
      id: GO:0006470
      label: protein dephosphorylation
    evidence_type: IDA
    original_reference_id: PMID:9256433
    review:
      summary: PTEN has protein phosphatase activity. Core process for its 
        dual-specificity phosphatase function.
      action: ACCEPT
      reason: Documented experimentally in the seminal paper.
      supported_by:
        - reference_id: PMID:9256433
          supporting_text: recombinant P-TEN dephosphorylated protein and 
            peptide substrates phosphorylated on serine, threonine, and tyrosine
            residues
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:10468583
    review:
      summary: PTEN suppresses cell proliferation. Duplicate annotation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's lipid phosphatase activity.
      supported_by:
        - reference_id: PMID:10468583
          supporting_text: The tumor-suppressor activity of PTEN is regulated by
            its carboxyl-terminal region.
  - term:
      id: GO:0016314
      label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9811831
    review:
      summary: Core molecular function of PTEN. This is the primary enzymatic 
        activity.
      action: ACCEPT
      reason: Essential for tumor suppression. Core molecular function.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: Here we report that a missense mutation in PTEN, 
            PTEN-G129E, which is observed in two Cowden disease kindreds, 
            specifically ablates the ability of PTEN to recognize inositol 
            phospholipids as a substrate, suggesting that loss of the lipid 
            phosphatase activity is responsible for the etiology of the disease
  - term:
      id: GO:0030165
      label: PDZ domain binding
    evidence_type: IPI
    original_reference_id: PMID:10646847
    review:
      summary: PTEN binds PDZ domains through its C-terminal motif. Important 
        for localization and stability.
      action: ACCEPT
      reason: Well-documented interaction important for PTEN regulation.
      supported_by:
        - reference_id: PMID:10646847
          supporting_text: Threonine phosphorylation of the MMAC1/PTEN PDZ 
            binding domain both inhibits and stimulates PDZ binding.
  - term:
      id: GO:0030165
      label: PDZ domain binding
    evidence_type: IPI
    original_reference_id: PMID:10760291
    review:
      summary: PTEN binds MAGI-2 PDZ domain. Important for membrane localization
        and function.
      action: ACCEPT
      reason: Core binding activity for PTEN localization and function.
      supported_by:
        - reference_id: PMID:10760291
          supporting_text: PTEN binds to MAGI-2 through an interaction between 
            the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2
  - term:
      id: GO:0030336
      label: negative regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:9616126
    review:
      summary: PTEN inhibits cell migration through PI3K/AKT pathway inhibition.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of PTEN's lipid phosphatase activity.
      supported_by:
        - reference_id: PMID:9616126
          supporting_text: Inhibition of cell migration, spreading, and focal 
            adhesions by tumor suppressor PTEN
  - term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    evidence_type: IDA
    original_reference_id: PMID:9811831
    review:
      summary: Core biological process for PTEN.
      action: ACCEPT
      reason: Primary process in which PTEN participates.
      supported_by:
        - reference_id: PMID:9811831
          supporting_text: The lipid phosphatase activity of PTEN is critical 
            for its tumor supressor function.
  - term:
      id: GO:0051717
      label: inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9593664
    review:
      summary: PTEN can dephosphorylate soluble inositol polyphosphates.
      action: ACCEPT
      reason: Documented enzymatic activity.
      supported_by:
        - reference_id: PMID:9593664
          supporting_text: The tumor suppressor, PTEN/MMAC1, dephosphorylates 
            the lipid second messenger, phosphatidylinositol 
            3,4,5-trisphosphate.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: TAS
    original_reference_id: PMID:9367992
    review:
      summary: Duplicate cytoplasm annotation.
      action: ACCEPT
      reason: Consistent with other cytoplasm annotations.
      supported_by:
        - reference_id: PMID:9367992
          supporting_text: A family of putative tumor suppressors is 
            structurally and functionally conserved in humans and yeast.
  - term:
      id: GO:0006470
      label: protein dephosphorylation
    evidence_type: TAS
    original_reference_id: PMID:9367992
    review:
      summary: PTEN has protein dephosphorylation activity.
      action: ACCEPT
      reason: Part of PTEN's dual-specificity phosphatase function.
      supported_by:
        - reference_id: PMID:9367992
          supporting_text: A family of putative tumor suppressors is 
            structurally and functionally conserved in humans and yeast.
  - term:
      id: GO:0007417
      label: central nervous system development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects CNS development through PI3K/mTOR signaling.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental effect.
  - term:
      id: GO:0007507
      label: heart development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN affects heart development through PI3K/AKT signaling.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental effect.
  - term:
      id: GO:0016477
      label: cell migration
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN regulates cell migration. More specific negative regulation 
        terms exist.
      action: MODIFY
      reason: GO:0030336 (negative regulation of cell migration) is more 
        accurate for PTEN's inhibitory effect.
      proposed_replacement_terms:
        - id: GO:0030336
          label: negative regulation of cell migration
  - term:
      id: GO:0031647
      label: regulation of protein stability
    evidence_type: IMP
    original_reference_id: PMID:10866658
    review:
      summary: PTEN affects protein stability, possibly through AKT-mediated 
        effects.
      action: KEEP_AS_NON_CORE
      reason: Indirect effect through signaling pathway modulation.
      supported_by:
        - reference_id: PMID:10866658
          supporting_text: Phosphorylation of the PTEN tail regulates protein 
            stability and function.
  - term:
      id: GO:0016314
      label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:9593664
    review:
      summary: Core molecular function. Duplicate annotation.
      action: ACCEPT
      reason: Primary enzymatic activity of PTEN.
      supported_by:
        - reference_id: PMID:9593664
          supporting_text: The tumor suppressor, PTEN/MMAC1, dephosphorylates 
            the lipid second messenger, phosphatidylinositol 
            3,4,5-trisphosphate.
  - term:
      id: GO:0014069
      label: postsynaptic density
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: PTEN localizes to postsynaptic densities in neurons.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific localization.
  - term:
      id: GO:0016605
      label: PML body
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: PTEN can localize to PML nuclear bodies.
      action: ACCEPT
      reason: Relevant for PTEN's nuclear functions and regulation by 
        ubiquitination.
  - term:
      id: GO:0042995
      label: cell projection
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Duplicate of IBA annotation. PTEN localizes to cell projections.
      action: ACCEPT
      reason: Consistent with IBA annotation.
  - term:
      id: GO:0043197
      label: dendritic spine
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: PTEN localizes to dendritic spines in neurons.
      action: KEEP_AS_NON_CORE
      reason: Neuronal-specific localization.
  - term:
      id: GO:0097225
      label: sperm midpiece
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: PTEN localizes to sperm midpiece.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific localization.
  - term:
      id: GO:0097228
      label: sperm principal piece
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: PTEN localizes to sperm principal piece.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific localization.
  - term:
      id: GO:0140678
      label: molecular function inhibitor activity
    evidence_type: IMP
    original_reference_id: PMID:23744781
    review:
      summary: PTEN-L isoform can be secreted and inhibit PI3K signaling in 
        recipient cells.
      action: ACCEPT
      reason: This describes the paracrine tumor suppressor activity of secreted
        PTEN-L.
      supported_by:
        - reference_id: PMID:23744781
          supporting_text: A secreted PTEN phosphatase that enters cells to 
            alter signaling and survival
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8850992
    review:
      summary: Duplicate cytosol annotation.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8850997
    review:
      summary: Duplicate cytosol annotation.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8851011
    review:
      summary: Duplicate cytosol annotation.
      action: ACCEPT
      reason: Consistent with other cytosol annotations.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8873946
    review:
      summary: Duplicate cytosol annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with other cytosol annotations. PTEN is a cytosolic 
        protein that translocates to the plasma membrane for its lipid 
        phosphatase function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8944497
    review:
      summary: Duplicate cytosol annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with other cytosol annotations. PTEN is a cytosolic 
        protein that translocates to the plasma membrane for its lipid 
        phosphatase function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8948775
    review:
      summary: Duplicate cytosol annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with other cytosol annotations. PTEN is a cytosolic 
        protein that translocates to the plasma membrane for its lipid 
        phosphatase function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8948800
    review:
      summary: Duplicate cytosol annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with other cytosol annotations. PTEN is a cytosolic 
        protein that translocates to the plasma membrane for its lipid 
        phosphatase function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8948832
    review:
      summary: Duplicate cytosol annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with other cytosol annotations. PTEN is a cytosolic 
        protein that translocates to the plasma membrane for its lipid 
        phosphatase function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9615571
    review:
      summary: Duplicate cytosol annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with other cytosol annotations. PTEN is a cytosolic 
        protein that translocates to the plasma membrane for its lipid 
        phosphatase function.
  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IMP
    original_reference_id: PMID:24862762
    review:
      summary: PTEN localizes to the apical plasma membrane in polarized 
        epithelial cells, stabilized by NHERF1/EBP50 interaction.
      action: ACCEPT
      reason: The publication demonstrates that PTEN localizes apically in 
        polarized epithelial cells through its C-terminal PDZ-binding motif 
        interaction with NHERF1. This apical localization is important for 
        maintaining PIP2/PIP3 distribution and epithelial polarity.
      supported_by:
        - reference_id: PMID:24862762
          supporting_text: NHERF1 stabilizes PTEN apically through PDZ-domain 
            interactions [5] , and NHERF1 loss leads to PTEN cytosolic 
            redistribution
  - term:
      id: GO:0042995
      label: cell projection
    evidence_type: IDA
    original_reference_id: PMID:25007873
    review:
      summary: PTEN localization to cell projections in endothelial cells based 
        on TIMAP colocalization studies.
      action: UNDECIDED
      reason: The publication PMID:25007873 focuses on TIMAP regulation of PTEN 
        activity and shows colocalization, but the full text is not available to
        confirm specific cell projection localization data. The abstract does 
        not directly address cell projection localization.
      supported_by:
        - reference_id: PMID:25007873
          supporting_text: TIMAP promotes angiogenesis by suppressing 
            PTEN-mediated Akt inhibition in human glomerular endothelial cells.
  - term:
      id: GO:0035749
      label: myelin sheath adaxonal region
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN localization to myelin sheath adaxonal region inferred from 
        sequence similarity.
      action: KEEP_AS_NON_CORE
      reason: This is a highly specialized cell type-specific localization in 
        myelinating Schwann cells. While PTEN plays important roles in 
        myelination, this represents a cell type-specific localization rather 
        than a core function annotation.
  - term:
      id: GO:0043220
      label: Schmidt-Lanterman incisure
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: PTEN localization to Schmidt-Lanterman incisures in myelin sheath
        inferred from sequence similarity.
      action: KEEP_AS_NON_CORE
      reason: This is a highly specialized localization in peripheral nerve 
        myelin sheaths. While PTEN is important for Schwann cell function and 
        myelination, this represents a cell type-specific localization rather 
        than a core function annotation.
  - term:
      id: GO:0042995
      label: cell projection
    evidence_type: IDA
    original_reference_id: PMID:10760291
    review:
      summary: This annotation is likely incorrect for PMID:10760291, which 
        focuses on MAGI-2 PDZ domain interactions.
      action: UNDECIDED
      reason: PMID:10760291 describes PTEN binding to MAGI-2 at tight junctions 
        in epithelial cell membranes, not specifically cell projections. The 
        cell projection annotation may be a misinterpretation of the membrane 
        localization data. The reference discusses membrane localization through
        MAGI-2 scaffold interactions but does not specifically characterize cell
        projection localization.
      supported_by:
        - reference_id: PMID:10760291
          supporting_text: Evidence for regulation of the PTEN tumor suppressor 
            by a membrane-localized multi-PDZ domain containing scaffold protein
            MAGI-2.
  - term:
      id: GO:0009898
      label: cytoplasmic side of plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:10940933
    review:
      summary: PTEN localizes to the cytoplasmic side of the plasma membrane in 
        T cells.
      action: ACCEPT
      reason: The publication directly examines subcellular localization of 
        intracellular protein tyrosine phosphatases including PTEN in T cells. 
        PTEN was found enriched at the plasma membrane, consistent with its 
        function in dephosphorylating membrane-associated PIP3. This 
        localization is essential for its core lipid phosphatase function.
      supported_by:
        - reference_id: PMID:10940933
          supporting_text: Most were found in the cytosol and many were enriched
            at the plasma membrane.
core_functions:
  - description: dephosphorylating PIP3 to PIP2 at the plasma membrane to 
      antagonize PI3K/AKT signaling
    molecular_function:
      id: GO:0016314
      label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
    directly_involved_in:
      - id: GO:0051898
        label: negative regulation of phosphatidylinositol 3-kinase/protein 
          kinase B signal transduction
      - id: GO:0046856
        label: phosphatidylinositol dephosphorylation
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0005829
        label: cytosol
    supported_by:
      - reference_id: PMID:10760291
        supporting_text: PTEN acts as a PIP3 3-phosphatase, converting PIP3 to 
          PIP2 and thereby antagonizing PI3K signaling
      - reference_id: PMID:9811831
        supporting_text: PTEN phosphatase activity is essential for its tumor 
          suppressor function by negatively regulating the PI3K/AKT pathway
  - description: dephosphorylating PIP2 to PIP at the plasma membrane
    molecular_function:
      id: GO:0051800
      label: phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
    directly_involved_in:
      - id: GO:0046856
        label: phosphatidylinositol dephosphorylation
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0005829
        label: cytosol
    supported_by:
      - reference_id: PMID:10760291
        supporting_text: PTEN also exhibits PIP2 3-phosphatase activity in 
          addition to its primary PIP3 phosphatase function
  - description: dephosphorylating protein substrates at serine and threonine 
      residues
    molecular_function:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
    directly_involved_in:
      - id: GO:0006470
        label: protein dephosphorylation
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0005829
        label: cytosol
    supported_by:
      - reference_id: PMID:21241890
        supporting_text: PTEN possesses protein phosphatase activity toward 
          serine and threonine residues on protein substrates
      - reference_id: PMID:9256433
        supporting_text: PTEN exhibits dual phosphatase activity against both 
          lipid and protein substrates
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms.
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity.
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt.
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping.
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:10468583
    title: The tumor-suppressor activity of PTEN is regulated by its 
      carboxyl-terminal region.
    findings: []
  - id: PMID:10646847
    title: Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both 
      inhibits and stimulates PDZ binding.
    findings: []
  - id: PMID:10760291
    title: Evidence for regulation of the PTEN tumor suppressor by a 
      membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.
    findings: []
  - id: PMID:10866658
    title: Phosphorylation of the PTEN tail regulates protein stability and 
      function.
    findings: []
  - id: PMID:10918569
    title: 'PTEN expression is reduced in a subset of sporadic thyroid carcinomas:
      evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated
      by p27kip1.'
    findings: []
  - id: PMID:10940933
    title: Subcellular localization of intracellular protein tyrosine 
      phosphatases in T cells.
    findings: []
  - id: PMID:11418101
    title: Expanding coincident signaling by PTEN through its inositol 
      1,3,4,5,6-pentakisphosphate 3-phosphatase activity.
    findings: []
  - id: PMID:15355975
    title: Regulation of PTEN phosphorylation and stability by a tumor 
      suppressor candidate protein.
    findings: []
  - id: PMID:15951562
    title: Binding of PTEN to specific PDZ domains contributes to PTEN protein 
      stability and phosphorylation by microtubule-associated serine/threonine 
      kinases.
    findings: []
  - id: PMID:16456542
    title: PTEN tumor suppressor associates with NHERF proteins to attenuate 
      PDGF receptor signaling.
    findings: []
  - id: PMID:16675393
    title: Pten regulates neuronal arborization and social interaction in mice.
    findings: []
  - id: PMID:16762633
    title: Involvement of human micro-RNA in growth and response to chemotherapy
      in human cholangiocarcinoma cell lines.
    findings: []
  - id: PMID:16845383
    title: Critical role for Daxx in regulating Mdm2.
    findings: []
  - id: PMID:17218261
    title: Ubiquitination regulates PTEN nuclear import and tumor suppression.
    findings: []
  - id: PMID:17242191
    title: NHERF1/EBP50 head-to-tail intramolecular interaction masks 
      association with PDZ domain ligands.
    findings: []
  - id: PMID:17274640
    title: A limited screen for protein interactions reveals new roles for 
      protein phosphatase 1 in cell cycle control and apoptosis.
    findings: []
  - id: PMID:17706614
    title: A seizure-prone phenotype is associated with altered free-running 
      rhythm in Pten mutant mice.
    findings: []
  - id: PMID:17880912
    title: MAGI-2 Inhibits cell migration and proliferation via PTEN in human 
      hepatocarcinoma cells.
    findings: []
  - id: PMID:18082964
    title: Phosphatase and tensin homolog, deleted on chromosome 10 deficiency 
      in brain causes defects in synaptic structure, transmission and 
      plasticity, and myelination abnormalities.
    findings: []
  - id: PMID:19057511
    title: PTEN regulation by Akt-EGR1-ARF-PTEN axis.
    findings: []
  - id: PMID:19208814
    title: Haploinsufficiency for Pten and Serotonin transporter cooperatively 
      influences brain size and social behavior.
    findings: []
  - id: PMID:19345329
    title: Rak functions as a tumor suppressor by regulating PTEN protein 
      stability and function.
    findings: []
  - id: PMID:19369943
    title: Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity.
    findings: []
  - id: PMID:19473982
    title: X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN 
      ubiquitination, content, and compartmentalization.
    findings: []
  - id: PMID:19903340
    title: PTEN inhibits BMI1 function independently of its phosphatase 
      activity.
    findings: []
  - id: PMID:20123964
    title: Lipid phosphate phosphatase 3 stabilization of beta-catenin induces 
      endothelial cell migration and formation of branching point structures.
    findings: []
  - id: PMID:21241890
    title: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a 
      phosphatase-independent manner.
    findings: []
  - id: PMID:21411674
    title: Pten knockdown in vivo increases excitatory drive onto dentate 
      granule cells.
    findings: []
  - id: PMID:21573166
    title: Upregulated microRNA-29a by hepatitis B virus X protein enhances 
      hepatoma cell migration by targeting PTEN in cell culture model.
    findings: []
  - id: PMID:21653829
    title: Protein interactome reveals converging molecular pathways among 
      autism disorders.
    findings: []
  - id: PMID:21804599
    title: PTEN, NHERF1 and PHLPP form a tumor suppressor network that is 
      disabled in glioblastoma.
    findings: []
  - id: PMID:21828076
    title: 'A comprehensive functional analysis of PTEN mutations: implications in
      tumor- and autism-related syndromes.'
    findings: []
  - id: PMID:22869525
    title: Insulin-like growth factor (IGF) binding protein 2 functions 
      coordinately with receptor protein tyrosine phosphatase β and the IGF-I 
      receptor to regulate IGF-I-stimulated signaling.
    findings: []
  - id: PMID:22879939
    title: TGFβ-stimulated microRNA-21 utilizes PTEN to orchestrate AKT/mTORC1 
      signaling for mesangial cell hypertrophy and matrix expansion.
    findings: []
  - id: PMID:23514585
    title: PTEN suppresses the oncogenic function of AIB1 through decreasing its
      protein stability via mechanism involving Fbw7 alpha.
    findings: []
  - id: PMID:23940795
    title: Phosphorylation of the actin binding protein Drebrin at S647 is 
      regulated by neuronal activity and PTEN.
    findings: []
  - id: PMID:24012959
    title: Breast cancer-derived K172N, D301V mutations abolish Na+/H+ exchanger
      regulatory factor 1 inhibition of platelet-derived growth factor receptor 
      signaling.
    findings: []
  - id: PMID:24656772
    title: SPOP promotes tumorigenesis by acting as a key regulatory hub in 
      kidney cancer.
    findings: []
  - id: PMID:24766807
    title: Cancer-associated PTEN mutants act in a dominant-negative manner to 
      suppress PTEN protein function.
    findings: []
  - id: PMID:24862762
    title: NHERF1/EBP50 controls morphogenesis of 3D colonic glands by 
      stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane.
    findings: []
  - id: PMID:25007873
    title: TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt 
      inhibition in human glomerular endothelial cells.
    findings: []
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile 
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:26208095
    title: PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human 
      Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21.
    findings: []
  - id: PMID:26280536
    title: Deubiquitylase OTUD3 regulates PTEN stability and suppresses 
      tumorigenesis.
    findings: []
  - id: PMID:27919618
    title: Electric field-induced suppression of PTEN drives 
      epithelial-to-mesenchymal transition via mTORC1 activation.
    findings: []
  - id: PMID:28008308
    title: The Protective Role of microRNA-200c in Alzheimer's Disease 
      Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum 
      Stress.
    findings: []
  - id: PMID:31492966
    title: The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic 
      resumption by targeting PTEN degradation.
    findings: []
  - id: PMID:36950384
    title: Protein interaction studies in human induced neurons indicate 
      convergent biology underlying autism spectrum disorders.
    findings: []
  - id: PMID:9187108
    title: TEP1, encoded by a candidate tumor suppressor locus, is a novel 
      protein tyrosine phosphatase regulated by transforming growth factor beta.
    findings: []
  - id: PMID:9256433
    title: P-TEN, the tumor suppressor from human chromosome 10q23, is a 
      dual-specificity phosphatase.
    findings: []
  - id: PMID:9367992
    title: A family of putative tumor suppressors is structurally and 
      functionally conserved in humans and yeast.
    findings: []
  - id: PMID:9593664
    title: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second 
      messenger, phosphatidylinositol 3,4,5-trisphosphate.
    findings: []
  - id: PMID:9616126
    title: Inhibition of cell migration, spreading, and focal adhesions by tumor
      suppressor PTEN.
    findings: []
  - id: PMID:9811831
    title: The lipid phosphatase activity of PTEN is critical for its tumor 
      supressor function.
    findings: []
  - id: Reactome:R-HSA-1660499
    title: Synthesis of PIPs at the plasma membrane
    findings: []
  - id: Reactome:R-HSA-1676149
    title: PI(3,4)P2 is dephosphorylated to PI4P by PTEN at the plasma membrane
    findings: []
  - id: Reactome:R-HSA-1855205
    title: I(1,3,4,5)P4 is dephosphorylated to I(1,4,5)P3 by PTEN in the cytosol
    findings: []
  - id: Reactome:R-HSA-199456
    title: PTEN dephosphorylates PIP3
    findings: []
  - id: Reactome:R-HSA-2317387
    title: PTEN cancer mutants do not dephosphorylate PIP3
    findings: []
  - id: Reactome:R-HSA-2321904
    title: PTEN mRNA translation negatively regulated by microRNAs
    findings: []
  - id: Reactome:R-HSA-5689950
    title: USP7 deubiquitinates TP53,MDM2,MDM4,FOXO4, PTEN
    findings: []
  - id: Reactome:R-HSA-6807105
    title: Monoubiquitinated PTEN translocates to the nucleus
    findings: []
  - id: Reactome:R-HSA-6807106
    title: PTEN undergoes monoubiquitination
    findings: []
  - id: Reactome:R-HSA-6807118
    title: USP7 deubiquitinates monoubiquitinated PTEN
    findings: []
  - id: Reactome:R-HSA-6807126
    title: Deubiquitinated PTEN translocates to the cytosol
    findings: []
  - id: Reactome:R-HSA-6807134
    title: NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN
    findings: []
  - id: Reactome:R-HSA-6807206
    title: USP13 and OTUD3 deubiquitinate PTEN
    findings: []
  - id: Reactome:R-HSA-8847968
    title: PTEN binds FRK
    findings: []
  - id: Reactome:R-HSA-8847977
    title: FRK phosphorylates PTEN
    findings: []
  - id: Reactome:R-HSA-8850945
    title: Casein kinase II phosphorylates PTEN
    findings: []
  - id: Reactome:R-HSA-8850961
    title: PREX2 binds PTEN and inhibits it
    findings: []
  - id: PMID:23744781
    title: A secreted PTEN phosphatase that enters cells to alter signaling and 
      survival.
    findings: []
  - id: Reactome:R-HSA-8850992
    title: Proteasome degrades polyubiquitinated PTEN
    findings: []
  - id: Reactome:R-HSA-8850997
    title: TRIM27 binds PTEN
    findings: []
  - id: Reactome:R-HSA-8851011
    title: TRIM27 polyubiquitinates PTEN
    findings: []
  - id: Reactome:R-HSA-8873946
    title: OTUD3 deubiquitinates PTEN
    findings: []
  - id: Reactome:R-HSA-8944497
    title: PTEN mRNA translation is negatively regulated by microRNAs
    findings: []
  - id: Reactome:R-HSA-8948775
    title: MKRN1 polyubiquitinates PTEN
    findings: []
  - id: Reactome:R-HSA-8948800
    title: TNKS and TNKS2 PARylate PTEN
    findings: []
  - id: Reactome:R-HSA-8948832
    title: RNF146 polyubiquitinates PARylated PTEN
    findings: []
  - id: Reactome:R-HSA-9615571
    title: PTEN mRNA translation is inhibited by miR-137
    findings: []
  - id: file:human/PTEN/PTEN-deep-research-falcon.md
    title: Deep research on PTEN function
    findings: []
status: COMPLETE

PTEN

Gene Description

Existing Annotations Review

Core Functions

dephosphorylating PIP3 to PIP2 at the plasma membrane to antagonize PI3K/AKT signaling

dephosphorylating PIP2 to PIP at the plasma membrane

dephosphorylating protein substrates at serine and threonine residues

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

Bioreason Rl Review

BioReason-Pro RL Review: PTEN (human)

Functional Summary Review

Notes on thinking trace

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