Neurofibromin (NF1) is a large multidomain tumor suppressor protein of 2839 amino acids that functions as a negative regulator of the RAS-MAPK signaling pathway. The protein contains a central GTPase-activating protein (GAP) related domain (GRD, residues 1251-1482) that stimulates the intrinsic GTPase activity of RAS proteins, accelerating their conversion from active GTP-bound to inactive GDP-bound states. This Ras-GAP activity is the primary mechanism by which neurofibromin acts as a tumor suppressor. The protein also contains a SEC14/CRAL-TRIO lipid-binding domain (residues 1580-1738) that binds glycerophospholipids, particularly phosphatidylethanolamine and phosphatidylcholine with monounsaturated fatty acids, and an adjacent PH-like domain. Loss-of-function mutations cause neurofibromatosis type 1 (NF1), characterized by cafe-au-lait spots, neurofibromas, and increased cancer risk. Neurofibromin also regulates cAMP/PKA signaling in neurons and modulates cytoskeletal organization through effects on Rho/ROCK pathways.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: GTPase activator activity is the defining molecular function of neurofibromin. The GRD domain (residues 1251-1482) contains an arginine finger at position 1276 that is crucial for stabilizing the transition state during RAS GTP hydrolysis. This activity has been confirmed by multiple IDA annotations. Reason: This is the core molecular function of NF1. The RasGAP activity is well-established through biochemical studies and structural analysis. IBA annotation is appropriate as this function is conserved across species and supported by phylogenetic inference. |
| GO:1902531 regulation of intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: NF1 regulates intracellular signaling primarily through its negative regulation of RAS-MAPK and PI3K-AKT-mTOR pathways, as well as positive regulation of cAMP/PKA signaling in neurons. Reason: This is a core biological process for NF1. As a major RasGAP, neurofibromin is a central regulator of intracellular signal transduction, particularly the RAS-MAPK cascade. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation based on combined automated methods. This annotation is consistent with the IDA and IBA annotations for the same term. Reason: This IEA annotation is accurate and consistent with experimental evidence. Duplicate annotations with different evidence codes are acceptable. Supporting Evidence: UniProt:P21359 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: NF1 has a bipartite nuclear localization signal (residues 2555-2571) and has been shown to be actively transported to the nucleus. Reason: Nuclear localization is supported by experimental evidence. UniProt notes nuclear localization based on immunofluorescence studies (PMID:14988005). |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | ACCEPT | Summary: Nucleolar localization is documented in UniProt based on subcellular localization studies. Reason: Nucleolar localization is supported by experimental evidence in UniProt annotation. Supporting Evidence: UniProt:P21359 |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization is consistent with NF1's function in regulating membrane-associated RAS proteins. Reason: Plasma membrane localization is essential for NF1's function in regulating RAS at the membrane. This is supported by IDA annotation from HPA and by the interaction with SPRED proteins that recruit NF1 to the membrane. |
| GO:0008289 lipid binding | IEA GO_REF:0000043 | MODIFY | Summary: NF1 binds phospholipids via its CRAL-TRIO/SEC14 domain (residues 1580-1738). More specific terms (phosphatidylethanolamine binding, phosphatidylcholine binding) are available and annotated with IDA evidence. Reason: While lipid binding is accurate, the annotation should be replaced with the more specific child terms that have IDA evidence: phosphatidylethanolamine binding (GO:0008429) and phosphatidylcholine binding (GO:0031210). Proposed replacements: phosphatidylethanolamine binding phosphatidylcholine binding Supporting Evidence: PMID:17187824 The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: NF1 is involved in numerous developmental processes as evidenced by the pleiotropic phenotypes of NF1 patients and knockout mice. This is a very broad term. Reason: While accurate, this is an extremely broad term that does not capture the specific developmental processes affected by NF1. More specific annotations exist for neural, glial, cardiovascular, and other developmental processes. Supporting Evidence: UniProt:P21359 |
| GO:0098793 presynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Presynaptic localization is inferred from GO inter-ontology links. NF1 is highly expressed in neurons and regulates synaptic function. Reason: Presynaptic localization is plausible given NF1's role in neurons and synaptic plasticity, but the primary localization is cytoplasmic/membrane. This represents a specialized subcellular context rather than core localization. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0005515 protein binding | IPI PMID:11356864 Bipartite interaction between neurofibromatosis type I prote... | MODIFY | Summary: This annotation refers to NF1 interaction with syndecan transmembrane heparan sulfate proteoglycans. The generic 'protein binding' term is uninformative. Reason: Protein binding is too vague. Should be replaced with a more specific MF term describing the interaction with syndecans or heparan sulfate proteoglycans. Proposed replacements: proteoglycan binding Supporting Evidence: PMID:11356864 Bipartite interaction between neurofibromatosis type I protein (neurofibromin) and syndecan transmembrane heparan sulfate proteoglycans. |
| GO:0005515 protein binding | IPI PMID:16374483 Neurofibromatosis type 1 protein and amyloid precursor prote... | MODIFY | Summary: This annotation refers to NF1 interaction with APP (amyloid precursor protein) and colocalization with melanosomes in melanocytes. Reason: Protein binding is uninformative. The specific interaction with APP could be captured with a more specific term or documented as a protein-protein interaction. Proposed replacements: identical protein binding Supporting Evidence: PMID:16374483 Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes. |
| GO:0005515 protein binding | IPI PMID:26635368 Interaction between a Domain of the Negative Regulator of th... | MODIFY | Summary: This annotation refers to NF1-GRD interaction with SPRED1. SPRED proteins recruit NF1 to the plasma membrane to regulate RAS. Reason: This interaction is functionally important for NF1's RasGAP activity. A more specific term should capture the regulatory nature of this interaction. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:26635368 Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. |
| GO:0005515 protein binding | IPI PMID:30194290 Interrogating the protein interactomes of RAS isoforms ident... | REMOVE | Summary: This annotation refers to NF1 interaction with KRAS in a proteomics study of RAS isoform interactomes. Reason: This interaction is better captured by the GTPase activator activity annotation. NF1 binding to RAS-GTP is the substrate for its GAP activity, not a separate protein binding function. Supporting Evidence: PMID:30194290 Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability. |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is a central negative regulator of the MAPK cascade through its RasGAP activity. Reason: Involvement in MAPK cascade is a core function of NF1. By stimulating RAS GTPase activity, NF1 negatively regulates the downstream RAF-MEK-ERK cascade. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0001649 osteoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 patients often have bone abnormalities. NF1 regulates osteoblast function through RAS-MAPK signaling. Reason: Bone abnormalities are part of the NF1 phenotype, but osteoblast differentiation is a downstream pleiotropic effect, not a core function of NF1. Supporting Evidence: UniProt:P21359 |
| GO:0001656 metanephros development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kidney development involvement inferred from mouse knockout studies. Reason: This is a developmental process affected by NF1 loss but not a core function. |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1-deficient cells show altered responses to hypoxia, likely through RAS-MAPK effects. Reason: Response to hypoxia is a secondary effect of NF1's regulation of RAS signaling. |
| GO:0001889 liver development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Liver development involvement inferred from mouse knockout studies. Reason: This is a developmental process affected by NF1 loss but not a core function. |
| GO:0001937 negative regulation of endothelial cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1-deficient endothelial cells show increased proliferation. There is IMP evidence for this annotation from PMID:17404841 and PMID:16648142. Reason: This annotation is supported by experimental evidence (IMP) and reflects NF1's tumor suppressor function in regulating cell proliferation. Supporting Evidence: PMID:17404841 Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. |
| GO:0001938 positive regulation of endothelial cell proliferation | IEA GO_REF:0000107 | REMOVE | Summary: This conflicts with the negative regulation annotation. NF1 loss leads to increased endothelial proliferation, meaning NF1 normally negatively regulates this process. Reason: This annotation appears to be incorrect. NF1 is a negative regulator of cell proliferation. The positive regulation annotation likely reflects the increased proliferation seen with NF1 loss, which is backwards from the correct annotation. |
| GO:0001952 regulation of cell-matrix adhesion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects cell-matrix adhesion through its regulation of RAS-Rho crosstalk and cytoskeletal organization. Reason: Cell-matrix adhesion is affected by NF1 through downstream effects on the cytoskeleton, but this is not a core function. |
| GO:0001953 negative regulation of cell-matrix adhesion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Specific direction of regulation for cell-matrix adhesion. Reason: Secondary effect of NF1's regulation of RAS signaling and cytoskeletal organization. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Neurofibromin is predominantly cytoplasmic, consistent with its function in regulating membrane-associated RAS. Reason: Cytoplasmic localization is well-established and represents the primary localization of the protein. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0007154 cell communication | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cell communication is an extremely broad term. NF1 affects signaling pathways. Reason: This term is too general. More specific terms like MAPK cascade and Ras protein signal transduction better capture NF1's role in signaling. |
| GO:0007265 Ras protein signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is a central regulator of Ras signaling through its RasGAP activity. Reason: This is a core biological process for NF1. The protein directly regulates RAS activity by stimulating GTP hydrolysis. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0007406 negative regulation of neuroblast proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is a tumor suppressor that negatively regulates cell proliferation in neural tissues. Reason: This is consistent with NF1's role as a tumor suppressor in neural tissues. NF1 patients develop neurofibromas from aberrantly proliferating neural crest cells. Supporting Evidence: UniProt:P21359 |
| GO:0007420 brain development | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is highly expressed in brain and NF1 patients have cognitive deficits and brain abnormalities. Reason: Brain development is a well-documented biological process involving NF1. NF1 patients frequently have T2 hyperintensities and cognitive deficits. Supporting Evidence: PMID:17299016 T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0007422 peripheral nervous system development | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is critical for PNS development. Neurofibromas are tumors of peripheral nerves. Reason: NF1 is highly expressed in Schwann cells and peripheral nerve tumors are a hallmark of NF1 disease. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0007507 heart development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 plays a role in cardiovascular development. NF1 knockout mice have cardiac defects. Reason: Cardiac development is affected by NF1 loss, but this is a secondary effect rather than a core function of the protein. |
| GO:0007519 skeletal muscle tissue development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects muscle development through RAS-MAPK signaling. Reason: Muscle development involvement is a secondary effect of NF1's regulation of growth factor signaling pathways. |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: As a tumor suppressor, NF1 negatively regulates cell proliferation. Reason: This is a core function of NF1 as a tumor suppressor. Loss of NF1 leads to increased cell proliferation and tumor formation. Supporting Evidence: UniProt:P21359 |
| GO:0008542 visual learning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 patients have cognitive deficits including learning difficulties. Reason: Visual learning deficits are part of the cognitive phenotype in NF1, but this is a downstream consequence of NF1's role in neuronal signaling, not a core function. |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects apoptotic pathways through its regulation of RAS-MAPK and PI3K-AKT signaling. Reason: Apoptosis regulation is a downstream effect of NF1's modulation of growth factor signaling pathways. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: NF1 affects gene expression through its regulation of RAS-MAPK signaling, which influences transcription factor activity. Reason: This is too broad. Gene expression changes are downstream consequences of NF1's regulation of signaling pathways, not a direct function. |
| GO:0014044 Schwann cell development | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is highly expressed in Schwann cells and regulates their proliferation and differentiation. Neurofibromas arise from Schwann cells. Reason: Schwann cell development is a core context for NF1 function. The protein is most highly expressed in Schwann cells and loss of NF1 in these cells leads to neurofibroma formation. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0016525 negative regulation of angiogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 negatively regulates angiogenesis through effects on endothelial cell proliferation. Reason: NF1 loss leads to increased angiogenesis in tumors. This is supported by experimental evidence. Supporting Evidence: PMID:17404841 Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. |
| GO:0021510 spinal cord development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects spinal cord development through its role in neural development. Reason: Spinal cord development is affected by NF1 but is not a core function. |
| GO:0021764 amygdala development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects amygdala development as part of its broader role in brain development. Reason: Amygdala development is a specific aspect of brain development affected by NF1. |
| GO:0021897 forebrain astrocyte development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 regulates glial cell development including astrocytes. Reason: Astrocyte development is affected by NF1 through its regulation of RAS-MAPK signaling in glial progenitors. |
| GO:0021915 neural tube development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects neural tube development as part of its role in embryonic development. Reason: Neural tube development is a developmental process affected by NF1. |
| GO:0021987 cerebral cortex development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects cerebral cortex development, contributing to cognitive phenotypes in patients. Reason: Cortical development is part of NF1's broader role in brain development. |
| GO:0022011 myelination in peripheral nervous system | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates Schwann cell function which is critical for myelination. Reason: Myelination is directly relevant to NF1's high expression in Schwann cells. Schwann cells are the myelinating glia of the PNS. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0030036 actin cytoskeleton organization | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 affects actin cytoskeleton through RAS-Rho crosstalk and Rho/ROCK pathways. Reason: Cytoskeletal regulation is an important downstream effect of NF1's regulation of RAS signaling, particularly through effects on Rho GTPases. Supporting Evidence: file:human/NF1/NF1-deep-research-cyberian.md Loss of NF1 impacts Rho/ROCK-linked cytoskeletal programs. |
| GO:0030198 extracellular matrix organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects ECM organization through effects on cell adhesion and matrix interactions. Reason: ECM organization is a downstream effect of NF1's regulation of cell signaling. |
| GO:0030199 collagen fibril organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects collagen organization as part of its effects on ECM. Reason: Collagen organization is a secondary effect rather than a core function. |
| GO:0030325 adrenal gland development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects adrenal gland development. NF1 patients can develop pheochromocytomas. Reason: Adrenal development is affected by NF1 loss but is not a core function. |
| GO:0030336 negative regulation of cell migration | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 negatively regulates cell migration through effects on RAS-MAPK and cytoskeleton. Supported by IMP evidence from PMID:16648142. Reason: Cell migration regulation is important for NF1's tumor suppressor function and is supported by experimental evidence. Supporting Evidence: PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. |
| GO:0032228 regulation of synaptic transmission, GABAergic | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects GABAergic transmission as part of its role in neuronal function. Reason: Synaptic transmission regulation is a specialized neuronal function of NF1. |
| GO:0034605 cellular response to heat | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 may affect cellular stress responses. Reason: Heat response is likely a secondary effect of NF1's regulation of signaling pathways. |
| GO:0035021 negative regulation of Rac protein signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects Rac signaling through RAS-Rho crosstalk. Reason: Rac regulation is a secondary effect of NF1's primary RasGAP function. |
| GO:0042060 wound healing | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects wound healing through effects on cell proliferation and migration. Reason: Wound healing is affected by NF1 through its regulation of cell proliferation and migration, but is not a core function. |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: As a tumor suppressor, NF1 regulates cell proliferation. Reason: Regulation of cell proliferation is a core biological process for NF1 as a tumor suppressor. Supporting Evidence: UniProt:P21359 |
| GO:0042308 negative regulation of protein import into nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 may affect nuclear protein import through effects on signaling. Reason: Nuclear import regulation is a secondary effect of signaling pathway modulation. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 can promote apoptosis by limiting survival signals through RAS-PI3K-AKT. Reason: As a tumor suppressor, NF1 can promote apoptosis by limiting pro-survival signaling through the RAS-PI3K-AKT pathway. Supporting Evidence: UniProt:P21359 |
| GO:0043408 regulation of MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is a central regulator of the MAPK cascade through RasGAP activity. Reason: MAPK cascade regulation is a core function of NF1 as a RasGAP. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0043409 negative regulation of MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 negatively regulates the MAPK cascade by stimulating RAS GTPase activity. Supported by IMP evidence from PMID:16648142. Reason: This is a core function of NF1. By accelerating RAS-GTP hydrolysis, NF1 limits downstream MAPK signaling. Supporting Evidence: PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0043473 pigmentation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 affects pigmentation. Cafe-au-lait spots are a hallmark of NF1 disease. Reason: Pigmentation abnormalities (cafe-au-lait spots) are a diagnostic feature of NF1 disease, indicating involvement in pigmentation. Supporting Evidence: UniProt:P21359 |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 affects PI3K-AKT signaling through its regulation of RAS, which activates PI3K. Reason: PI3K-AKT pathway regulation is a downstream consequence of NF1's RasGAP activity and contributes to its tumor suppressor function. Supporting Evidence: file:human/NF1/NF1-deep-research-cyberian.md Neurofibromin accelerates hydrolysis of RAS-bound GTP to GDP, thereby restraining RAS effector signaling (RAF-MEK-ERK; PI3K-AKT-mTOR). |
| GO:0043525 positive regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 can promote neuronal apoptosis under certain conditions. Reason: Neuronal apoptosis regulation is a context-dependent function of NF1. |
| GO:0045124 regulation of bone resorption | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects bone metabolism through effects on osteoclasts and osteoblasts. Reason: Bone resorption regulation is a secondary effect of NF1's growth factor signaling modulation. |
| GO:0045671 negative regulation of osteoclast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects osteoclast differentiation as part of its role in bone development. Reason: Osteoclast regulation is a secondary effect of NF1's signaling functions. |
| GO:0045685 regulation of glial cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates glial cell differentiation, consistent with its high expression in Schwann cells and oligodendrocytes. Reason: Glial cell differentiation regulation is a core function given NF1's expression in and effects on Schwann cells, astrocytes, and oligodendrocytes. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0045765 regulation of angiogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates angiogenesis through effects on endothelial cell proliferation and migration. Supported by IMP evidence from PMID:17404841. Reason: Angiogenesis regulation is well-documented for NF1 and is supported by experimental evidence. Supporting Evidence: PMID:17404841 Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. |
| GO:0046580 negative regulation of Ras protein signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 is a direct negative regulator of RAS signaling through its RasGAP activity. Reason: This is the core function of NF1. As a RasGAP, neurofibromin directly stimulates RAS GTPase activity, converting RAS-GTP to RAS-GDP and terminating signaling. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0046929 negative regulation of neurotransmitter secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects neurotransmitter release as part of its neuronal functions. Reason: Neurotransmitter secretion regulation is a specialized neuronal function. |
| GO:0048147 negative regulation of fibroblast proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 negatively regulates fibroblast proliferation as part of its tumor suppressor function. Also annotated with ISS evidence. Reason: Fibroblast proliferation regulation is consistent with NF1's tumor suppressor function. Neurofibromas contain fibroblasts. Supporting Evidence: UniProt:P21359 |
| GO:0048169 regulation of long-term neuronal synaptic plasticity | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates synaptic plasticity through effects on RAS-MAPK and cAMP signaling. Reason: Synaptic plasticity regulation is consistent with NF1's role in learning and memory. NF1 patients have cognitive deficits. Supporting Evidence: PMID:17299016 T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. file:human/NF1/NF1-deep-research-cyberian.md Neurofibromin also positively regulates adenylyl cyclase/cAMP-PKA signaling in neurons and astrocytes. |
| GO:0048485 sympathetic nervous system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects sympathetic nervous system development. Reason: SNS development is a specialized developmental process affected by NF1. |
| GO:0048593 camera-type eye morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 affects eye development. NF1 patients can have Lisch nodules. Reason: Eye abnormalities (Lisch nodules) are a diagnostic feature of NF1, indicating involvement in eye development. Supporting Evidence: UniProt:P21359 |
| GO:0048712 negative regulation of astrocyte differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 negatively regulates astrocyte differentiation. Reason: Astrocyte differentiation regulation is consistent with NF1's role in glial cell development and its effects on gliogenesis. Supporting Evidence: file:human/NF1/NF1-deep-research-cyberian.md Neurofibromin also positively regulates adenylyl cyclase/cAMP-PKA signaling in neurons and astrocytes. |
| GO:0048715 negative regulation of oligodendrocyte differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates oligodendrocyte differentiation. Reason: NF1 is highly expressed in oligodendrocytes, so regulation of their differentiation is expected. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0048745 smooth muscle tissue development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects smooth muscle development through RAS-MAPK signaling. Reason: Smooth muscle development is a secondary effect of NF1's signaling functions. |
| GO:0048820 hair follicle maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects hair follicle development. Reason: Hair follicle maturation is a secondary effect of NF1's developmental functions. |
| GO:0048844 artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects vascular development including artery morphogenesis. Reason: Artery morphogenesis is a developmental process affected by NF1. |
| GO:0048853 forebrain morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects forebrain development as part of its role in brain development. Reason: Forebrain morphogenesis is part of NF1's broader role in brain development. |
| GO:0060291 long-term synaptic potentiation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 affects LTP through its regulation of RAS-MAPK and cAMP signaling in neurons. Reason: LTP regulation is consistent with NF1's role in learning and memory and cognitive deficits in NF1 patients. Supporting Evidence: file:human/NF1/NF1-deep-research-cyberian.md Neurofibromin also positively regulates adenylyl cyclase/cAMP-PKA signaling in neurons and astrocytes, consistent with cognitive phenotypes in NF1. |
| GO:0061534 gamma-aminobutyric acid secretion, neurotransmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects GABAergic neurotransmission. Reason: GABA secretion is a specialized neuronal function of NF1. |
| GO:0061535 glutamate secretion, neurotransmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects glutamatergic neurotransmission. Reason: Glutamate secretion is a specialized neuronal function of NF1. |
| GO:0070372 regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates ERK1/2 cascade through its negative regulation of RAS-MAPK signaling. Reason: ERK1/2 cascade regulation is a direct downstream effect of NF1's RasGAP activity. Supporting Evidence: file:human/NF1/NF1-deep-research-cyberian.md Neurofibromin accelerates hydrolysis of RAS-bound GTP to GDP, thereby restraining RAS effector signaling (RAF-MEK-ERK; PI3K-AKT-mTOR). |
| GO:0098597 observational learning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects observational learning as part of its cognitive functions. Reason: Observational learning is a specific cognitive function affected by NF1. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 is found at glutamatergic synapses. Reason: Glutamatergic synapse localization is a specialized neuronal context for NF1. |
| GO:0099175 regulation of postsynapse organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 affects postsynaptic organization through effects on cytoskeleton and signaling. Reason: Postsynapse organization is a specialized neuronal function of NF1. |
| GO:1900271 regulation of long-term synaptic potentiation | IEA GO_REF:0000107 | ACCEPT | Summary: NF1 regulates LTP through RAS-MAPK and cAMP signaling. Reason: LTP regulation is important for NF1's role in learning and memory. Supporting Evidence: PMID:17299016 T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. |
| GO:2001241 positive regulation of extrinsic apoptotic signaling pathway in absence of ligand | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF1 can promote apoptosis by limiting survival signals. Reason: Apoptosis regulation is a downstream effect of NF1's tumor suppressor function. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm localization based on immunofluorescence data. Reason: Supported by experimental evidence. NF1 has a nuclear localization signal and is found in the nucleus. Supporting Evidence: PMID:14988005 Neurofibromin is actively transported to the nucleus. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane localization based on immunofluorescence data from HPA. Reason: Plasma membrane localization is essential for NF1's function in regulating membrane-associated RAS proteins. Supporting Evidence: UniProt:P21359 |
| GO:0005515 protein binding | IPI PMID:34626534 SPRED2 loss-of-function causes a recessive Noonan syndrome-l... | MODIFY | Summary: This refers to NF1 interaction with SPRED2. SPRED proteins recruit NF1 to the plasma membrane. Reason: Protein binding is uninformative. The SPRED interaction is important for NF1 membrane recruitment and should be captured with a more specific term. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:34626534 SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6802837 | ACCEPT | Summary: Cytosolic localization from Reactome pathway annotation. Reason: Cytosolic localization is consistent with NF1's predominantly cytoplasmic distribution. Supporting Evidence: Reactome:R-HSA-6802837 NF1 is a RAS GTPase activating protein (GAP) that promotes the conversion of the active RAS:GTP to the inactive RAS:GDP form |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658424 | ACCEPT | Summary: Duplicate cytosol annotation from Reactome. Reason: Duplicate annotations with different references are acceptable. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658430 | ACCEPT | Summary: Duplicate cytosol annotation from Reactome NF1 degradation pathway. Reason: Duplicate annotations with different references are acceptable. |
| GO:0005515 protein binding | IPI PMID:23027611 5-HT(6) receptor recruitment of mTOR as a mechanism for pert... | MODIFY | Summary: This refers to NF1 interaction with HTR6 (serotonin receptor 5-HT6). Reason: Protein binding is uninformative. This specific interaction with a serotonin receptor is relevant to NF1's role in cognition. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:23027611 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: Membrane localization from high-throughput proteomics of NK cells. Reason: Membrane association is consistent with NF1's function at the plasma membrane. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. |
| GO:0005096 GTPase activator activity | IDA PMID:2121371 The NF1 locus encodes a protein functionally related to mamm... | ACCEPT | Summary: Direct experimental demonstration that NF1 has GTPase activator activity. This is the landmark paper establishing NF1's RasGAP function. Reason: This IDA annotation is the gold standard for NF1's core molecular function. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0008429 phosphatidylethanolamine binding | IDA PMID:17187824 The sec14 homology module of neurofibromin binds cellular gl... | ACCEPT | Summary: Direct experimental evidence that NF1's SEC14 domain binds phosphatidylethanolamine. Reason: This IDA annotation is based on structural and biochemical studies of the SEC14 domain lipid binding. Supporting Evidence: PMID:17187824 The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex. |
| GO:0031210 phosphatidylcholine binding | IDA PMID:17187824 The sec14 homology module of neurofibromin binds cellular gl... | ACCEPT | Summary: Direct experimental evidence that NF1's SEC14 domain binds phosphatidylcholine. Reason: This IDA annotation is based on structural and biochemical studies. Supporting Evidence: PMID:17187824 The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex. |
| GO:0043547 positive regulation of GTPase activity | IDA PMID:2121371 The NF1 locus encodes a protein functionally related to mamm... | ACCEPT | Summary: Direct evidence that NF1 positively regulates RAS GTPase activity. Reason: This is the core biological process annotation corresponding to NF1's RasGAP molecular function. Supporting Evidence: PMID:2121371 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658231 | ACCEPT | Summary: Cytosol localization from Reactome RAS GAPs pathway. Reason: Consistent with NF1's cytoplasmic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658435 | ACCEPT | Summary: Cytosol localization from Reactome RAS binding pathway. Reason: Consistent with NF1's cytoplasmic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658438 | ACCEPT | Summary: Cytosol localization from Reactome SPRED-NF1 pathway. Reason: Consistent with NF1's cytoplasmic localization. |
| GO:0048147 negative regulation of fibroblast proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity transfer. Reason: Consistent with NF1's tumor suppressor function and the IEA annotation. |
| GO:0000165 MAPK cascade | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for MAPK cascade involvement. Reason: Consistent with NF1's core function in regulating RAS-MAPK signaling. |
| GO:0001649 osteoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for osteoblast differentiation. Reason: Bone effects are secondary to NF1's signaling functions. |
| GO:0001656 metanephros development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for kidney development. Reason: Kidney development is a secondary effect. |
| GO:0001666 response to hypoxia | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for hypoxia response. Reason: Hypoxia response is a secondary effect. |
| GO:0001889 liver development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for liver development. Reason: Liver development is a secondary effect. |
| GO:0001952 regulation of cell-matrix adhesion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for cell-matrix adhesion regulation. Reason: Cell-matrix adhesion is a secondary effect. |
| GO:0007154 cell communication | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS annotation for cell communication. Reason: Too broad - more specific signaling terms are available. |
| GO:0007265 Ras protein signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for Ras signaling. Reason: Core function of NF1. |
| GO:0007406 negative regulation of neuroblast proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for neuroblast proliferation regulation. Reason: Consistent with NF1's tumor suppressor function in neural tissues. |
| GO:0007420 brain development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for brain development. Reason: Brain development is a well-documented NF1 function. |
| GO:0007422 peripheral nervous system development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for PNS development. Reason: PNS development is a core context for NF1 function. |
| GO:0007507 heart development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for heart development. Reason: Heart development is a secondary effect. |
| GO:0008542 visual learning | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for visual learning. Reason: Visual learning is a specific cognitive function. |
| GO:0014044 Schwann cell development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for Schwann cell development. Reason: Schwann cell development is a core context for NF1. |
| GO:0021510 spinal cord development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for spinal cord development. Reason: Spinal cord development is a secondary effect. |
| GO:0021897 forebrain astrocyte development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for astrocyte development. Reason: Astrocyte development is a specialized glial function. |
| GO:0021987 cerebral cortex development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for cortex development. Reason: Cortex development is part of brain development. |
| GO:0022011 myelination in peripheral nervous system | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for PNS myelination. Reason: Myelination is relevant to NF1's Schwann cell expression. |
| GO:0030036 actin cytoskeleton organization | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for cytoskeleton organization. Reason: Cytoskeleton regulation is an important downstream effect. |
| GO:0030198 extracellular matrix organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for ECM organization. Reason: ECM organization is a secondary effect. |
| GO:0030199 collagen fibril organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for collagen organization. Reason: Collagen organization is a secondary effect. |
| GO:0030325 adrenal gland development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for adrenal development. Reason: Adrenal development is a secondary effect. |
| GO:0042060 wound healing | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for wound healing. Reason: Wound healing is a secondary effect. |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for apoptosis regulation. Reason: Apoptosis regulation is part of NF1's tumor suppressor function. |
| GO:0043409 negative regulation of MAPK cascade | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for negative MAPK regulation. Reason: Core function of NF1 as a RasGAP. |
| GO:0043473 pigmentation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for pigmentation. Reason: Cafe-au-lait spots are diagnostic for NF1. |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for PI3K-AKT signaling. Reason: PI3K-AKT regulation is downstream of NF1's RasGAP activity. |
| GO:0043525 positive regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for neuronal apoptosis. Reason: Neuronal apoptosis is a context-dependent function. |
| GO:0045124 regulation of bone resorption | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for bone resorption regulation. Reason: Bone metabolism is a secondary effect. |
| GO:0045685 regulation of glial cell differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for glial differentiation. Reason: Glial cell regulation is a core context for NF1. |
| GO:0048485 sympathetic nervous system development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for SNS development. Reason: SNS development is a secondary effect. |
| GO:0048593 camera-type eye morphogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for eye development. Reason: Eye abnormalities are diagnostic for NF1. |
| GO:0048715 negative regulation of oligodendrocyte differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for oligodendrocyte differentiation. Reason: NF1 is expressed in oligodendrocytes. |
| GO:0048745 smooth muscle tissue development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for smooth muscle development. Reason: Smooth muscle development is a secondary effect. |
| GO:0048844 artery morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for artery morphogenesis. Reason: Vascular development is a secondary effect. |
| GO:0048853 forebrain morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for forebrain morphogenesis. Reason: Part of broader brain development. |
| GO:0050890 cognition | IMP PMID:17299016 T2 hyperintensities in children with neurofibromatosis type ... | ACCEPT | Summary: IMP annotation for cognition based on studies of NF1 patients with T2 hyperintensities and cognitive deficits. Reason: Cognitive deficits are a well-documented feature of NF1 and there is experimental evidence for this annotation. Supporting Evidence: PMID:17299016 T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. |
| GO:0001937 negative regulation of endothelial cell proliferation | IMP PMID:17404841 Angiogenic expression profile of normal and neurofibromin-de... | ACCEPT | Summary: IMP annotation showing NF1 negatively regulates endothelial proliferation. Reason: Supported by experimental evidence in NF1-deficient Schwann cells. Supporting Evidence: PMID:17404841 Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. |
| GO:0005096 GTPase activator activity | IDA PMID:1568247 Somatic mutations in the neurofibromatosis 1 gene in human t... | ACCEPT | Summary: IDA annotation for GTPase activator activity from tumor mutation studies. Reason: Experimental evidence supporting NF1's core RasGAP function. Supporting Evidence: PMID:1568247 Somatic mutations in the neurofibromatosis 1 gene in human tumors. |
| GO:0005096 GTPase activator activity | IDA PMID:1570015 Aberrant regulation of ras proteins in malignant tumour cell... | ACCEPT | Summary: IDA annotation showing aberrant RAS regulation in NF1 patient tumors. Reason: Experimental evidence for NF1's RasGAP function from patient tumor analysis. Supporting Evidence: PMID:1570015 Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. |
| GO:0005634 nucleus | ISS PMID:1550670 The protein product of the neurofibromatosis type 1 gene is ... | ACCEPT | Summary: ISS annotation for nuclear localization. Reason: Nuclear localization is supported by experimental evidence. Supporting Evidence: PMID:14988005 Neurofibromin is actively transported to the nucleus. |
| GO:0005737 cytoplasm | ISS PMID:1550670 The protein product of the neurofibromatosis type 1 gene is ... | ACCEPT | Summary: ISS annotation for cytoplasmic localization. Reason: Cytoplasmic localization is well-established. Supporting Evidence: PMID:1550670 The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. |
| GO:0030424 axon | IDA PMID:1550670 The protein product of the neurofibromatosis type 1 gene is ... | ACCEPT | Summary: IDA annotation for axonal localization in neurons. Reason: Axonal localization is supported by immunohistochemistry in the original paper. Supporting Evidence: PMID:1550670 Neurofibromin is most abundant in the nervous system. Immunostaining of tissue sections indicates that neurons, oligodendrocytes, and nonmyelinating Schwann cells contain neurofibromin |
| GO:0030425 dendrite | IDA PMID:1550670 The protein product of the neurofibromatosis type 1 gene is ... | ACCEPT | Summary: IDA annotation for dendritic localization in neurons. Reason: Dendritic localization is consistent with NF1's high expression in neurons. Supporting Evidence: PMID:1550670 Neurofibromin is most abundant in the nervous system. Immunostaining of tissue sections indicates that neurons, oligodendrocytes, and nonmyelinating Schwann cells contain neurofibromin |
| GO:0043535 regulation of blood vessel endothelial cell migration | IMP PMID:17404841 Angiogenic expression profile of normal and neurofibromin-de... | ACCEPT | Summary: IMP annotation for endothelial migration regulation. Reason: Supported by experimental evidence from NF1-deficient cells. Supporting Evidence: PMID:17404841 Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. |
| GO:0045765 regulation of angiogenesis | IMP PMID:17404841 Angiogenic expression profile of normal and neurofibromin-de... | ACCEPT | Summary: IMP annotation for angiogenesis regulation. Reason: Supported by experimental evidence. Supporting Evidence: PMID:17404841 Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. |
| GO:0001937 negative regulation of endothelial cell proliferation | IMP PMID:16648142 Neurofibroma-associated growth factors activate a distinct s... | ACCEPT | Summary: IMP annotation from endothelial cell studies. Reason: Experimental evidence for NF1's role in endothelial proliferation control. Supporting Evidence: PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. |
| GO:0030336 negative regulation of cell migration | IMP PMID:16648142 Neurofibroma-associated growth factors activate a distinct s... | ACCEPT | Summary: IMP annotation for cell migration regulation. Reason: Supported by experimental evidence from NF1-deficient cells. Supporting Evidence: PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:16648142 Neurofibroma-associated growth factors activate a distinct s... | ACCEPT | Summary: IMP annotation for MAPK cascade negative regulation. Reason: Core function of NF1, supported by experimental evidence. Supporting Evidence: PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. |
| GO:0043547 positive regulation of GTPase activity | IMP PMID:16648142 Neurofibroma-associated growth factors activate a distinct s... | ACCEPT | Summary: IMP annotation for positive regulation of GTPase activity. Reason: Core function of NF1 as a RasGAP. Supporting Evidence: PMID:16648142 Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. |
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Download this section (compressed HTML)Q: What is the precise mechanism by which the SEC14 lipid-binding domain modulates NF1 function? Does lipid binding affect RasGAP activity, membrane localization, or protein stability?
Q: What is the relative contribution of RAS-MAPK inhibition versus cAMP regulation to NF1's neuronal functions and cognitive phenotypes?
Q: Are there tissue-specific isoforms or post-translational modifications of NF1 that confer specialized functions in different cell types?
Experiment: Structure-function analysis of SEC14 domain mutants to determine effects on NF1 localization, stability, and RasGAP activity. This would clarify the functional role of the lipid-binding domain.
Hypothesis: SEC14 domain lipid binding regulates NF1 membrane localization and/or stability.
Type: biochemistry
Experiment: Cell type-specific knockout studies in neurons vs astrocytes vs Schwann cells to dissect NF1's role in each cell type and clarify tissue-specific functions.
Hypothesis: NF1 has distinct functions in different neural cell types.
Type: genetic
Experiment: Phosphoproteomic analysis of NF1 to identify kinases that regulate NF1 activity and stability under different conditions. NF1 has many phosphorylation sites with unknown regulatory significance.
Hypothesis: Specific kinases regulate NF1 activity in response to growth factor signaling.
Type: proteomics
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