PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase type 1 beta, a membrane-associated lipid kinase whose core function is ATP-dependent phosphorylation of PI4P to generate PI(4,5)P2/PIP2. PI(4,5)P2 supports membrane signaling, actin remodeling, adhesion, vesicle trafficking, and autophagic lysosome reformation. Broader WNT/PI3K pathway signaling and uropod localization are secondary contexts relative to the PI4P 5-kinase/PIP2 biosynthetic role.
Definition: The process in which nascent lysosomes are regenerated from autolysosomal membranes following autophagy, including autolysosome tubule initiation, membrane remodeling, and proto-lysosome budding.
Justification: The ALR literature and PN curation need a term more specific than broad lysosome organization for proteins such as PIP5K1B that regulate autolysosomal membrane composition and tubulation.
Parent term: lysosome organization
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
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GO:0046854
phosphatidylinositol phosphate biosynthetic process
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: PIP5K1B contributes directly to phosphatidylinositol phosphate biosynthesis by producing PI(4,5)P2 from PI4P.
Reason: The process-level term is broad but appropriate for the core PI phosphate biosynthetic function.
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0005829
cytosol
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: PIP5K1B is a cytosolic enzyme that associates with cellular membranes, including plasma membrane and endomembrane contexts where phosphoinositide substrates reside. The falcon deep research reinforces the plasma membrane as the principal site where PIP5K1B generates PI(4,5)P2.
Reason: Retain as a supported membrane location for PIP5K1B catalytic activity and PN-relevant membrane remodeling contexts.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
PIP5K1B localizes primarily to the cytoplasmic face of the plasma membrane, where it carries out its principal function of generating PI(4,5)P2
|
|
GO:0012505
endomembrane system
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: PIP5K1B is a cytosolic enzyme that associates with cellular membranes, including plasma membrane and endomembrane contexts where phosphoinositide substrates reside.
Reason: Retain as a supported membrane location for PIP5K1B catalytic activity and PN-relevant membrane remodeling contexts.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0016308
1-phosphatidylinositol-4-phosphate 5-kinase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: This is the core PIP5K1B molecular function: phosphorylation of PI4P at the 5 position to generate PI(4,5)P2/PIP2. The falcon deep research independently describes PI4P as the predominant physiological substrate, with PI3P phosphorylation reported only as an in vitro side activity, consistent with treating the PI3P-using Reactome side reactions as non-core.
Reason: Retain as the specific catalytic function for this type I PIP5 kinase.
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
PIP5K1B catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PI4P, PtdIns4P) to generate phosphatidylinositol 4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
PIP5K1B exhibits primary specificity for PI4P as its physiological substrate
|
|
GO:0046488
phosphatidylinositol metabolic process
|
IEA
GO_REF:0000002 |
MODIFY |
Summary: The annotation captures phosphatidylinositol metabolism, but it is broader than the specific PI phosphate biosynthetic role of PIP5K1B.
Reason: Replace the broad phosphatidylinositol metabolic/biosynthetic process with phosphatidylinositol phosphate biosynthetic process.
Proposed replacements:
phosphatidylinositol phosphate biosynthetic process
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0051896
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: PI3K/AKT pathway effects are downstream of phosphoinositide metabolism and are secondary to the direct PIP5K1B lipid kinase function. The falcon deep research explains the mechanistic basis: PI(4,5)P2 generated by PIP5K1B is the immediate substrate for class I PI3Ks that produce PI(3,4,5)P3, so any influence on PI3K/AKT signaling is indirect via product supply rather than a direct regulatory role.
Reason: Keep as non-core pathway context rather than a defining PIP5K1B process; the direct gene-level role is PI4P 5-kinase activity and PI phosphate biosynthesis.
Proposed replacements:
phosphatidylinositol phosphate biosynthetic process
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
PI(4,5)P2 produced by PIP5K1B serves as the immediate substrate for class I phosphatidylinositol 3-kinases (PI3Ks), which phosphorylate PI(4,5)P2 at the 3-position to generate phosphatidylinositol 3,4,5-trisphosphate
|
|
GO:0052742
phosphatidylinositol kinase activity
|
IEA
GO_REF:0000002 |
MODIFY |
Summary: Phosphatidylinositol kinase activity is true but too general for PIP5K1B, whose defining activity is PI4P 5-kinase activity.
Reason: Use the specific 1-phosphatidylinositol-4-phosphate 5-kinase activity term.
Proposed replacements:
1-phosphatidylinositol-4-phosphate 5-kinase activity
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0006661
phosphatidylinositol biosynthetic process
|
TAS
Reactome:R-HSA-1660499 |
MODIFY |
Summary: The annotation captures phosphatidylinositol metabolism, but it is broader than the specific PI phosphate biosynthetic role of PIP5K1B.
Reason: Replace the broad phosphatidylinositol metabolic/biosynthetic process with phosphatidylinositol phosphate biosynthetic process.
Proposed replacements:
phosphatidylinositol phosphate biosynthetic process
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0051896
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
TAS
Reactome:R-HSA-6811558 |
KEEP AS NON CORE |
Summary: PI3K/AKT pathway effects are downstream of phosphoinositide metabolism and are secondary to the direct PIP5K1B lipid kinase function.
Reason: Keep as non-core pathway context rather than a defining PIP5K1B process; the direct gene-level role is PI4P 5-kinase activity and PI phosphate biosynthesis.
Proposed replacements:
phosphatidylinositol phosphate biosynthetic process
|
|
GO:0000285
1-phosphatidylinositol-3-phosphate 5-kinase activity
|
TAS
Reactome:R-HSA-1676134 |
KEEP AS NON CORE |
Summary: Reactome assigns this side-reaction/substrate context to PIP5K1B, but it is not the defining physiological activity. The falcon deep research notes that PI3P phosphorylation by type I PIP5Ks is observed in vitro, while PI4P remains the predominant cellular substrate.
Reason: Keep as non-core biochemical/pathway context and prioritize the PI4P to PI(4,5)P2 reaction as core.
Supporting Evidence:
Reactome:R-HSA-1676134
PIP5K1B
file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
While in vitro studies show that Type I PIP5Ks can also phosphorylate phosphatidylinositol 3-phosphate (PI3P) to generate PI(3,4)P2 and PI(3,5)P2, PI4P remains the predominant cellular substrate for PI(4,5)P2 synthesis
|
|
GO:0016308
1-phosphatidylinositol-4-phosphate 5-kinase activity
|
TAS
Reactome:R-HSA-1676082 |
ACCEPT |
Summary: This is the core PIP5K1B molecular function: phosphorylation of PI4P at the 5 position to generate PI(4,5)P2/PIP2.
Reason: Retain as the specific catalytic function for this type I PIP5 kinase.
Supporting Evidence:
Reactome:R-HSA-1676082
phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate)
|
|
GO:0052810
1-phosphatidylinositol-5-kinase activity
|
TAS
Reactome:R-HSA-1675810 |
KEEP AS NON CORE |
Summary: Reactome assigns this side-reaction/substrate context to PIP5K1B, but it is not the defining physiological activity.
Reason: Keep as non-core biochemical/pathway context and prioritize the PI4P to PI(4,5)P2 reaction as core.
Supporting Evidence:
Reactome:R-HSA-1675810
PIP5K1B
|
|
GO:0052742
phosphatidylinositol kinase activity
|
TAS
Reactome:R-HSA-1675773 |
MODIFY |
Summary: Phosphatidylinositol kinase activity is true but too general for PIP5K1B, whose defining activity is PI4P 5-kinase activity.
Reason: Use the specific 1-phosphatidylinositol-4-phosphate 5-kinase activity term.
Proposed replacements:
1-phosphatidylinositol-4-phosphate 5-kinase activity
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0016308
1-phosphatidylinositol-4-phosphate 5-kinase activity
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: This is the core PIP5K1B molecular function: phosphorylation of PI4P at the 5 position to generate PI(4,5)P2/PIP2.
Reason: Retain as the specific catalytic function for this type I PIP5 kinase.
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0005886
plasma membrane
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: PIP5K1B is a cytosolic enzyme that associates with cellular membranes, including plasma membrane and endomembrane contexts where phosphoinositide substrates reside.
Reason: Retain as a supported membrane location for PIP5K1B catalytic activity and PN-relevant membrane remodeling contexts.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1675773 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1675810 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1676082 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1676134 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1676145 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-3772434 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-3772436 |
KEEP AS NON CORE |
Summary: Cytosol is a correct broad localization for PIP5K1B, but it does not capture the membrane-associated catalytic biology.
Reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P 5-kinase activity.
Supporting Evidence:
file:human/PIP5K1B/PIP5K1B-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Cell membrane
|
|
GO:0001931
uropod
|
IDA
PMID:20442317 An isoform-specific PDZ-binding motif targets type I PIP5 ki... |
KEEP AS NON CORE |
Summary: PIP5KIbeta localizes to the uropod in polarized leukocyte models through an isoform-specific C-terminal motif.
Reason: Keep as a supported cell-type-specific localization, not as the core function.
Supporting Evidence:
PMID:20442317
Its final 83 amino acids localize PIP5KIbeta to the uropod of chemotaxing neutrophils and T cells
PMID:20442317
interact with ezrin-radixin-moesin (ERM) proteins and EBP50
|
|
GO:0005515
protein binding
|
IPI
PMID:20442317 An isoform-specific PDZ-binding motif targets type I PIP5 ki... |
MARK AS OVER ANNOTATED |
Summary: The interaction evidence is real for uropod targeting, but generic protein binding is not informative for PIP5K1B function.
Reason: Replace generic binding with the mechanistic localization/adaptor context in narrative rather than retaining GO:0005515 as a reviewed function.
Proposed replacements:
uropod
Supporting Evidence:
PMID:20442317
Its final 83 amino acids localize PIP5KIbeta to the uropod of chemotaxing neutrophils and T cells
PMID:20442317
interact with ezrin-radixin-moesin (ERM) proteins and EBP50
|
|
GO:0016308
1-phosphatidylinositol-4-phosphate 5-kinase activity
|
NAS
PMID:8955136 Type I phosphatidylinositol-4-phosphate 5-kinases are distin... |
ACCEPT |
Summary: This is the core PIP5K1B molecular function: phosphorylation of PI4P at the 5 position to generate PI(4,5)P2/PIP2.
Reason: Retain as the specific catalytic function for this type I PIP5 kinase.
Supporting Evidence:
PMID:8955136
Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize phosphatidylinositol-4,5-bisphosphate
file:human/PIP5K1B/PIP5K1B-uniprot.txt
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
|
|
GO:0007040
lysosome organization
|
IMP
PMID:22885770 Clathrin and phosphatidylinositol-4,5-bisphosphate regulate ... |
NEW |
Summary: PIP5K1B has direct ALR-context evidence through the PI(4,5)P2 pathway required for autolysosome tubulation and proto-lysosome budding. GO lacks a specific ALR term in the local cache, so lysosome organization is the best current broad term.
Reason: Add a broad lysosome organization annotation for the experimentally supported autophagic lysosome reformation context, with a proposed new ALR-specific child term to avoid over-broad curation long term.
Supporting Evidence:
PMID:22885770
clathrin and phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulate ALR
PMID:22885770
initiation of autolysosome tubulation, and proto-lysosome budding during ALR
url:https://www.nature.com/articles/ncb2557
PIP5K1B is required for the initiation of ALR
file:human/PIP5K1B/PIP5K1B-notes.md
Figure 3 as "PIP5K1B is required for the initiation of ALR"
|
Q: Should GO add a specific autophagic lysosome reformation term under lysosome organization, and should PIP5K1B be annotated to that term instead of broad GO:0007040?
Suggested experts: Li Yu, Yongliang Rong
Q: Which PIP5K1B phosphoinositide substrate activities are physiologically important in vivo versus pathway-level or in vitro side reactions?
Suggested experts: Richard A. Anderson, Reactome phosphoinositide curator
Experiment: Rescue PIP5K1B-depleted cells during starvation-refeeding with wild-type, kinase-dead, and membrane-targeting mutants while quantifying ALR tubule initiation and proto-lysosome budding.
Hypothesis: PIP5K1B kinase activity and membrane recruitment are required for PI(4,5)P2-dependent autophagic lysosome reformation.
Type: genetic rescue/live-cell imaging
Experiment: Measure local PI(4,5)P2 dynamics on autolysosome-derived tubules using phosphoinositide reporters in cells depleted of PIP5K1B, PIP5K1A, or PIP5K1C.
Hypothesis: PIP5K1B supplies a local PI(4,5)P2 pool on ALR membranes that is not fully redundant with other type I PIP5K isoforms.
Type: lipid reporter imaging/RNAi
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.
PIP5K1B (phosphatidylinositol 4-phosphate 5-kinase type-1 beta, UniProt O14986) encodes a Type I phosphatidylinositol phosphate kinase, also referred to as PIP5KΞ², PIP5KIΞ², or by the older synonym STM-7. This gene is one of three paralogs in the human Type I PIP5K family, alongside PIP5K1A and PIP5K1C (jin2023lipidkinasespip5ks pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2). Type I PIP5Ks are lipid kinases responsible for generating the majority of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] at the plasma membrane in eukaryotic cells, distinguishing them from Type II PIPKs (PIP4Ks), which preferentially use phosphatidylinositol 5-phosphate as substrate (muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, balla2013phosphoinositidestinylipids pages 1-2).
Primary Catalytic Reaction: PIP5K1B catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PI4P, PtdIns4P) to generate phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2, PtdIns(4,5)P2] using ATP as the phosphate donor (roy2023pip5k1cphosphoinositidekinase pages 1-2, muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2). Specifically, the enzyme transfers a phosphate group to the 5-position of the inositol ring of PI4P, yielding the bis-phosphorylated product PI(4,5)P2 and ADP (muftuoglu2016mechanismofsubstrate pages 1-2, balla2013phosphoinositidestinylipids pages 1-2). This reaction represents the major synthetic route for cellular PI(4,5)P2, with Type I PIP5Ks producing the dominant pool of this critical signaling lipid at the plasma membrane (hansen2022membranemediateddimerizationpotentiates pages 1-2, balla2013phosphoinositidestinylipids pages 2-3).
Substrate Specificity: PIP5K1B exhibits primary specificity for PI4P as its physiological substrate, phosphorylating the 5-position hydroxyl group of the inositol headgroup (muftuoglu2016mechanismofsubstrate pages 1-2, liu2016theactivationloop pages 1-1). Crystallographic and mutagenesis studies on Type I PIP5K family members have revealed that substrate specificity is determined by two key structural elements: a specialized "specificity loop" (also called the activation loop) and a conserved monophosphate-binding site that recognizes the 4-phosphate moiety of PI4P (muftuoglu2016mechanismofsubstrate pages 1-2, liu2016theactivationloop pages 1-1). While in vitro studies show that Type I PIP5Ks can also phosphorylate phosphatidylinositol 3-phosphate (PI3P) to generate PI(3,4)P2 and PI(3,5)P2, PI4P remains the predominant cellular substrate for PI(4,5)P2 synthesis (muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2).
Structural and Mechanistic Insights: PIP5K1B belongs to the PIPK family of lipid kinases, which possess a catalytic domain with a protein kinase-like fold distinct from classical serine/threonine or tyrosine kinases (muftuoglu2016mechanismofsubstrate pages 1-2, hu2015resolutionofstructure pages 1-2). Crystal structures of Type I PIP5Ks reveal that these enzymes form side-to-side dimers, and dimerization enhances catalytic efficiency through mechanisms consistent with allosteric regulation (hansen2022membranemediateddimerizationpotentiates pages 1-2, hu2015resolutionofstructure pages 1-2). The enzyme requires membrane association for activity, and this membrane docking is mediated by an activation loop that functions as a membrane sensor (liu2016theactivationloop pages 1-1). NMR studies have shown that the activation loop, which is disordered in crystal structures, folds into an amphipathic helix upon association with membrane surfaces, and the hydrophobic face of this helix is essential for both kinase activity and membrane sensing (liu2016theactivationloop pages 1-1). The membrane-bound kinase can undergo protein density-dependent dimerization, which potentiates lipid kinase activity and creates a broad dynamic range of enzymatic activities coupled to the local density of PI(4,5)P2 and membrane-bound enzyme (hansen2022membranemediateddimerizationpotentiates pages 1-2).
PIP5K1B localizes primarily to the cytoplasmic face of the plasma membrane, where it carries out its principal function of generating PI(4,5)P2 (hansen2022membranemediateddimerizationpotentiates pages 1-2, wen2023regulationofphosphoinositide pages 1-3, balla2013phosphoinositidestinylipids pages 2-3). Studies of Type I PIP5K family members consistently demonstrate that these enzymes are targeted to the plasma membrane through multiple mechanisms: substrate recognition, electrostatic interactions with anionic lipids, and positive feedback through cooperative binding to their PI(4,5)P2 product (hansen2022membranemediateddimerizationpotentiates pages 1-2). Single-molecule studies on human PIP5KB have revealed that the enzyme exhibits cooperative membrane association with PI(4,5)P2-containing membranes, establishing a positive feedback loop during the PI4P phosphorylation reaction (hansen2022membranemediateddimerizationpotentiates pages 1-2). The amphipathic activation loop serves as a critical membrane sensor, enabling the kinase to detect and bind to membrane surfaces in an orientation conducive to lipid substrate processing (liu2016theactivationloop pages 1-1). While Type I PIP5K isoforms share plasma membrane localization, they may exhibit distinct spatiotemporal regulation and subcellular distributions that allow for isoform-specific functions (roy2023pip5k1cphosphoinositidekinase pages 1-2, kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2).
PIP5K1B functions within multiple interconnected signaling pathways through the generation and regulation of PI(4,5)P2 levels at the plasma membrane.
PI3K/Akt Signaling Pathway: PI(4,5)P2 produced by PIP5K1B serves as the immediate substrate for class I phosphatidylinositol 3-kinases (PI3Ks), which phosphorylate PI(4,5)P2 at the 3-position to generate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3, PIP3] (jin2023lipidkinasespip5ks pages 1-2, dieterle2014pdk1controlsupstream pages 1-2, balla2013phosphoinositidestinylipids pages 1-2). This conversion is central to the PI3K/Akt pathway, which regulates cell growth, proliferation, survival, and metabolism (dieterle2014pdk1controlsupstream pages 1-2). Studies have demonstrated that PIP5K activity influences PI3K signaling output by controlling substrate availability; for example, PDK1 (a downstream effector in this pathway) can negatively regulate PI3K class IA subunit expression through transcriptional feedback, and this regulation is modulated by PIP5K-dependent PI(4,5)P2 generation and PIP5K protein stability (dieterle2014pdk1controlsupstream pages 1-2, jin2023lipidkinasespip5ks pages 5-6). The PI3K/Akt pathway is frequently dysregulated in cancer, and recent literature identifies PIP5K family members, including PIP5K1B, as potential therapeutic targets in malignancies such as breast cancer (jin2023lipidkinasespip5ks pages 1-2, jin2023lipidkinasespip5ks pages 5-6).
Phospholipase C Signaling: PI(4,5)P2 at the plasma membrane is the substrate for phospholipase C (PLC) enzymes, which cleave PI(4,5)P2 to generate two critical second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (balla2013phosphoinositidestinylipids pages 1-2, balla2013phosphoinositidestinylipids pages 2-3). This pathway is activated downstream of G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), initiating calcium signaling and protein kinase C activation (balla2013phosphoinositidestinylipids pages 1-2). By controlling the plasma membrane pool of PI(4,5)P2, PIP5K1B indirectly regulates the magnitude and duration of PLC-mediated signaling responses.
Actin Cytoskeleton Regulation: PI(4,5)P2 plays a pivotal role in reorganizing the actin cytoskeleton in response to extracellular signals (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2, wen2023regulationofphosphoinositide pages 1-3, hou2025phosphoinositidesignalingat pages 1-2). The lipid directly binds to and regulates numerous actin-binding proteins, modulating actin polymerization, filament capping, and cross-linking. PI(4,5)P2 is essential for the formation and dynamics of cellular protrusions such as lamellipodia and filopodia, which are critical for cell migration (peng2021clic1recruitspip5k1ac pages 1-2, wen2023regulationofphosphoinositide pages 1-3, hou2025phosphoinositidesignalingat pages 1-2). Recent studies have shown that PIP5K recruitment to the leading edge of migrating cells generates PI(4,5)P2-rich microdomains that coordinate the extension of actin filaments and the formation of integrin-mediated cell-matrix adhesions (peng2021clic1recruitspip5k1ac pages 1-2). Specifically, membrane-targeted proteins can recruit PIP5Ks (including PIP5K1A and PIP5K1C) from the cytoplasm to the plasma membrane, where they locally produce PI(4,5)P2 to induce nascent adhesion formation and signaling for cytoskeleton extension during directional migration and tumor invasion (peng2021clic1recruitspip5k1ac pages 1-2).
T-cell Receptor Signaling and Immunological Synapse Formation: PIP5K1B (PIP5KΞ²) has been shown to play a specific, non-redundant role in T lymphocyte activation through its function at the immunological synapse (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2). PI(4,5)P2 is critical for T-cell activation, serving both as a substrate for second messenger generation and as a regulator of actin cytoskeleton remodeling necessary for clustering lipid rafts, T-cell receptors, and costimulatory molecules at the T cell-antigen presenting cell interface (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2). Studies demonstrate that CD28 costimulation induces the recruitment of PIP5KΞ² to the immunological synapse, where it regulates filamin A (FLNA) and lipid raft accumulation, as well as overall T-cell activation, in a manner that is not compensated by other PIP5K isoforms (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2). The functional specificity of PIP5KΞ² in this context depends on interactions with the guanine nucleotide exchange factor Vav1 and the C-terminal region of PIP5KΞ² (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2).
Endocytosis and Vesicle Trafficking: PI(4,5)P2 is a key regulator of endocytic processes, particularly clathrin-mediated endocytosis (wen2023regulationofphosphoinositide pages 1-3, balla2013phosphoinositidestinylipids pages 1-2, balla2013phosphoinositidestinylipids pages 2-3). The lipid recruits adaptor proteins and regulates the dynamics of endocytic vesicle formation and scission. Phosphoinositide signaling, including PIP5K-mediated PI(4,5)P2 generation, controls membrane dynamics and vesicular trafficking at multiple intracellular compartments (balla2013phosphoinositidestinylipids pages 1-2, baba2020emergingrolesof pages 1-2). Recent evidence also indicates roles for PI4P and PI(4,5)P2 in regulating multiple steps of autophagy, including autophagosome-lysosome fusion and reformation processes (baba2020emergingrolesof pages 1-2).
Ion Channel and Receptor Regulation: PI(4,5)P2 directly modulates the activity of numerous ion channels, pumps, and transporters at the plasma membrane (balla2013phosphoinositidestinylipids pages 1-2, balla2013phosphoinositidestinylipids pages 2-3). Many channels require PI(4,5)P2 binding for proper gating and function, and changes in local PI(4,5)P2 levels mediated by PIP5K activity can rapidly alter channel activity.
Through the generation of PI(4,5)P2, PIP5K1B participates in a wide array of biological processes central to cellular physiology:
Cell Motility and Migration: PI(4,5)P2 produced by PIP5Ks drives the formation of membrane protrusions and cell-matrix adhesions essential for directional cell migration (peng2021clic1recruitspip5k1ac pages 1-2, wen2023regulationofphosphoinositide pages 1-3, hou2025phosphoinositidesignalingat pages 1-2). The spatiotemporal coordination of PIP5K activity at the leading edge enables cells to extend lamellipodia/invadopodia and form nascent integrin-based adhesions (peng2021clic1recruitspip5k1ac pages 1-2).
Cell Adhesion: PIP5K-mediated PI(4,5)P2 synthesis regulates the formation and dynamics of cell-matrix adhesions by recruiting adhesion-complex components such as talin to the plasma membrane and activating integrin signaling (peng2021clic1recruitspip5k1ac pages 1-2, hou2025phosphoinositidesignalingat pages 1-2).
Immune Cell Function: In T lymphocytes, PIP5KΞ² controls the organization of the immunological synapse, including the recruitment of lipid rafts and signaling molecules necessary for effective T-cell activation and immune responses (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2).
Membrane Trafficking: PI(4,5)P2 regulates both endocytic and exocytic processes, controlling vesicle formation, trafficking, and fusion events throughout the endomembrane system (balla2013phosphoinositidestinylipids pages 1-2, balla2013phosphoinositidestinylipids pages 2-3, baba2020emergingrolesof pages 1-2).
Signal Transduction: As the substrate for PI3K and PLC, PI(4,5)P2 is positioned at a critical node in multiple receptor-mediated signaling cascades that control cell fate decisions, proliferation, survival, and metabolism (jin2023lipidkinasespip5ks pages 1-2, dieterle2014pdk1controlsupstream pages 1-2, balla2013phosphoinositidestinylipids pages 1-2).
Recent literature highlights the involvement of PIP5K family members, including PIP5K1B, in cancer biology and other diseases. A 2023 review identifies PIP5Ks and PIP4Ks as potential drug targets for breast cancer treatment, noting that the PI(4,5)P2 signaling axis is frequently dysregulated in malignancies (jin2023lipidkinasespip5ks pages 1-2). The review emphasizes that PI(4,5)P2 serves as a key activator of the frequently altered PI3K pathway in breast cancer, and that aberrant phosphoinositide metabolism contributes to tumor progression, metastasis, and drug resistance (jin2023lipidkinasespip5ks pages 1-2, jin2023lipidkinasespip5ks pages 5-6). Studies have also demonstrated that PIP5K activity is involved in cancer cell migration and invasion through the regulation of cytoskeletal dynamics and adhesion complexes (jin2023lipidkinasespip5ks pages 5-6, peng2021clic1recruitspip5k1ac pages 1-2). More broadly, dysregulation of phosphoinositide signaling has been implicated in diverse diseases including neurological disorders, metabolic diseases, and immune dysfunction (balla2013phosphoinositidestinylipids pages 1-2). A 2025 review discusses how phosphoinositide signaling at the cytoskeleton regulates cell dynamics, and how its dysregulation is implicated in diseases including cancer, highlighting therapeutic opportunities through targeted modulation of these pathways (hou2025phosphoinositidesignalingat pages 1-2).
PIP5K1B is a Type I phosphatidylinositol 4-phosphate 5-kinase that catalyzes the ATP-dependent phosphorylation of PI4P to generate PI(4,5)P2, the predominant signaling phosphoinositide at the plasma membrane. The enzyme localizes to the cytoplasmic face of the plasma membrane, where it uses an amphipathic activation loop as a membrane sensor to dock and process lipid substrates. Through the generation of PI(4,5)P2, PIP5K1B functions in multiple interconnected signaling pathways including PI3K/Akt signaling, phospholipase C signaling, actin cytoskeleton regulation, endocytosis, and ion channel modulation. PIP5KΞ² plays specific roles in T-cell receptor signaling and immunological synapse formation, demonstrating functional specialization among the three Type I PIP5K isoforms. The enzyme's regulation of PI(4,5)P2 levels is critical for cell migration, adhesion, membrane trafficking, and signal transduction. Recent research has identified PIP5K family members as potential therapeutic targets in cancer and other diseases characterized by dysregulated phosphoinositide metabolism.
| Feature | Description/Details (with citations) |
|---|---|
| Gene nomenclature | Official human gene: PIP5K1B; protein: phosphatidylinositol 4-phosphate 5-kinase type-1 beta / PIP5K1B / PIP5KΞ² / PIP5KIΞ²; older synonym STM7 is also associated with this beta isoform in the supplied target definition. The human Type I PIP5K family comprises three paralogs: PIP5K1A, PIP5K1B, and PIP5K1C (jin2023lipidkinasespip5ks pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, hu2015resolutionofstructure pages 1-2). |
| Protein classification and family | PIP5K1B is a Type I phosphatidylinositol phosphate kinase (PIP5K), i.e., a lipid kinase in the broader PIPK family. Type I PIPKs are the principal enzymes that synthesize most cellular and plasma-membrane PI(4,5)P2 from PI4P, distinguishing them from Type II PIPKs/PIP4Ks, which mainly use PI5P as substrate (muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, balla2013phosphoinositidestinylipids pages 1-2). |
| Enzymatic reaction catalyzed | Canonical reaction: phosphatidylinositol 4-phosphate [PI4P/PtdIns4P] + ATP β phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2/PtdIns(4,5)P2] + ADP. This is the defining reaction of Type I PIP5Ks and is the major synthetic route for PI(4,5)P2 in most cells (roy2023pip5k1cphosphoinositidekinase pages 1-2, muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, hu2015resolutionofstructure pages 1-2). |
| Substrate specificity | Primary physiological substrate is PI4P, phosphorylated at the 5-position of the inositol ring. Structural/biochemical studies of Type I PIPKs show that substrate specificity is determined by a specialized specificity loop/activation loop and a monophosphate-binding site; in vitro, Type I PIPKs can also show activity toward PI3P, but PI4P is the main cellular substrate for PI(4,5)P2 production (muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, liu2016theactivationloop pages 1-1). |
| Primary subcellular localization | Type I PIP5Ks function mainly at the cytoplasmic face of the plasma membrane, where they generate the dominant pool of PI(4,5)P2. Family studies emphasize membrane docking through substrate recognition, electrostatic interactions with anionic lipids, and product-assisted membrane association; recent work on human PIP5KB specifically discusses cooperative membrane association on PI(4,5)P2-containing membranes (muftuoglu2016mechanismofsubstrate pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, wen2023regulationofphosphoinositide pages 1-3). |
| Key structural features | PIP5K1B is expected to share the conserved PIPK catalytic core of Type I PIP5Ks, including a protein-kinase-like fold, a specificity/activation loop important for lipid-substrate recognition and localization, and a membrane-sensing amphipathic helix behavior within that activation loop. Structural work on Type I PIPKs also shows side-to-side dimerization that can enhance catalytic efficiency/allosteric regulation (liu2016theactivationloop pages 1-1, hu2015resolutionofstructure pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2). |
| Major signaling pathways involved | Through generation of PI(4,5)P2, PIP5K1B feeds multiple pathways: (1) PI3K-Akt signaling, because PI(4,5)P2 is the substrate for class I PI3K to make PI(3,4,5)P3; (2) PLC signaling, because PI(4,5)P2 is cleaved to IP3 and DAG; (3) membrane/cytoskeleton signaling, including actin remodeling, endocytosis, and receptor signaling; and (4) T-cell signaling, where PIP5KΞ² has a nonredundant role in immunological synapse organization (dieterle2014pdk1controlsupstream pages 1-2, kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, balla2013phosphoinositidestinylipids pages 1-2). |
| Biological processes regulated | PI(4,5)P2 produced by Type I PIP5Ks regulates actin cytoskeleton organization, lipid raft dynamics, immunological synapse assembly, endocytosis/exocytosis, ion channel and transporter regulation, vesicular trafficking, and cell migration/adhesion. In T cells, PIP5KΞ² controls recruitment of lipid rafts and filamin A to the immunological synapse; more broadly, phosphoinositide signaling organizes membraneβcytosol interfaces controlling motility and adhesion (kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2, hansen2022membranemediateddimerizationpotentiates pages 1-2, wen2023regulationofphosphoinositide pages 1-3, hou2025phosphoinositidesignalingat pages 1-2). |
| Disease associations mentioned in recent literature | Recent literature links the PIP5K/PIP4K axis to cancer biology and drug targeting, especially via altered PI(4,5)P2/PI3K signaling. A 2023 review identifies PIP5K family members as potential drug targets in breast cancer; broader phosphoinositide literature connects these enzymes to malignant signaling, trafficking, and cytoskeletal dysregulation. While recent papers more often emphasize PIP5K1A or PIP5K1C, PIP5K1B is part of the same disease-relevant enzymatic network and has been noted in cancer-cell phosphoinositide studies (jin2023lipidkinasespip5ks pages 1-2, jin2023lipidkinasespip5ks pages 5-6, wen2023regulationofphosphoinositide pages 1-3). |
Table: This table compiles the key functional annotation points for human PIP5K1B, including nomenclature, enzyme activity, localization, structural features, pathways, and disease relevance. It is useful as a concise evidence-backed reference for interpreting the proteinβs primary biochemical role.
References
(jin2023lipidkinasespip5ks pages 1-2): Yue Jin and Jian Xue. Lipid kinases pip5ks and pip4ks: potential drug targets for breast cancer. Frontiers in Oncology, Dec 2023. URL: https://doi.org/10.3389/fonc.2023.1323897, doi:10.3389/fonc.2023.1323897. This article has 11 citations.
(hansen2022membranemediateddimerizationpotentiates pages 1-2): Scott D Hansen, Albert A Lee, Benjamin R Duewell, and Jay T Groves. Membrane-mediated dimerization potentiates pip5k lipid kinase activity. Aug 2022. URL: https://doi.org/10.7554/elife.73747, doi:10.7554/elife.73747. This article has 36 citations and is from a domain leading peer-reviewed journal.
(muftuoglu2016mechanismofsubstrate pages 1-2): Yagmur Muftuoglu, Yi Xue, Xiang Gao, Dianqing Wu, and Ya Ha. Mechanism of substrate specificity of phosphatidylinositol phosphate kinases. Proceedings of the National Academy of Sciences, 113:8711-8716, Jul 2016. URL: https://doi.org/10.1073/pnas.1522112113, doi:10.1073/pnas.1522112113. This article has 49 citations and is from a highest quality peer-reviewed journal.
(balla2013phosphoinositidestinylipids pages 1-2): T. Balla. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiological reviews, 93 3:1019-137, Jul 2013. URL: https://doi.org/10.1152/physrev.00028.2012, doi:10.1152/physrev.00028.2012. This article has 1987 citations and is from a highest quality peer-reviewed journal.
(roy2023pip5k1cphosphoinositidekinase pages 1-2): Ajit Roy, Arup R. Chakraborty, Tyzoon Nomanbhoy, and Melvin L. DePamphilis. Pip5k1c phosphoinositide kinase deficiency distinguishes pikfyve-dependent cancer cells from non-malignant cells. Mar 2023. URL: https://doi.org/10.1080/15548627.2023.2182594, doi:10.1080/15548627.2023.2182594. This article has 14 citations and is from a domain leading peer-reviewed journal.
(balla2013phosphoinositidestinylipids pages 2-3): T. Balla. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiological reviews, 93 3:1019-137, Jul 2013. URL: https://doi.org/10.1152/physrev.00028.2012, doi:10.1152/physrev.00028.2012. This article has 1987 citations and is from a highest quality peer-reviewed journal.
(liu2016theactivationloop pages 1-1): Aizhuo Liu, Dexin Sui, Dianqing Wu, and Jian Hu. The activation loop of pip5k functions as a membrane sensor essential for lipid substrate processing. Science Advances, Nov 2016. URL: https://doi.org/10.1126/sciadv.1600925, doi:10.1126/sciadv.1600925. This article has 44 citations and is from a highest quality peer-reviewed journal.
(hu2015resolutionofstructure pages 1-2): Jian Hu, Qianying Yuan, Xue Kang, Yuanbo Qin, Lin Li, Ya Ha, and Dianqing Wu. Resolution of structure of pip5k1a reveals molecular mechanism for its regulation by dimerization and dishevelled. Nature Communications, Sep 2015. URL: https://doi.org/10.1038/ncomms9205, doi:10.1038/ncomms9205. This article has 68 citations and is from a highest quality peer-reviewed journal.
(wen2023regulationofphosphoinositide pages 1-3): Tianmu Wen, Narendra Thapa, Vincent L. Cryns, and Richard A. Anderson. Regulation of phosphoinositide signaling by scaffolds at cytoplasmic membranes. Biomolecules, 13:1297, Aug 2023. URL: https://doi.org/10.3390/biom13091297, doi:10.3390/biom13091297. This article has 20 citations.
(kallikourdis2016phosphatidylinositol4phosphate5kinase pages 1-2): Marinos Kallikourdis, Anna Elisa Trovato, Giuliana Roselli, Michela Muscolini, Nicla Porciello, Loretta Tuosto, and Antonella Viola. Phosphatidylinositol 4-phosphate 5-kinase Ξ² controls recruitment of lipid rafts into the immunological synapse. The Journal of Immunology, 196:1955-1963, Feb 2016. URL: https://doi.org/10.4049/jimmunol.1501788, doi:10.4049/jimmunol.1501788. This article has 32 citations.
(dieterle2014pdk1controlsupstream pages 1-2): Alexandra M. Dieterle, P. BΓΆhler, Hildegard Keppeler, S. Alers, N. Berleth, Stefan Driessen, N. Hieke, S. Pietkiewicz, Antje S. LΓΆffler, C. Peter, Alex Gray, Nick R. Leslie, H. Shinohara, Tomohiro Kurosaki, M. Engelke, J. Wienands, M. Bonin, Sebastian Wesselborg, and B. Stork. Pdk1 controls upstream pi3k expression and pip3 generation. Oncogene, 33:3043-3053, Jun 2014. URL: https://doi.org/10.1038/onc.2013.266, doi:10.1038/onc.2013.266. This article has 69 citations and is from a domain leading peer-reviewed journal.
(jin2023lipidkinasespip5ks pages 5-6): Yue Jin and Jian Xue. Lipid kinases pip5ks and pip4ks: potential drug targets for breast cancer. Frontiers in Oncology, Dec 2023. URL: https://doi.org/10.3389/fonc.2023.1323897, doi:10.3389/fonc.2023.1323897. This article has 11 citations.
(hou2025phosphoinositidesignalingat pages 1-2): Xiaoting Hou, Yu Chen, Noah D. Carrillo, Vincent L. Cryns, Richard A. Anderson, Jichao Sun, Songlin Wang, and Mo Chen. Phosphoinositide signaling at the cytoskeleton in the regulation of cell dynamics. Cell Death & Disease, Apr 2025. URL: https://doi.org/10.1038/s41419-025-07616-x, doi:10.1038/s41419-025-07616-x. This article has 26 citations and is from a peer-reviewed journal.
(peng2021clic1recruitspip5k1ac pages 1-2): Jei-Ming Peng, Sheng-Hsuan Lin, Ming-Chin Yu, and Sen-Yung Hsieh. Clic1 recruits pip5k1a/c to induce cell-matrix adhesions for tumor metastasis. Journal of Clinical Investigation, Jan 2021. URL: https://doi.org/10.1172/jci133525, doi:10.1172/jci133525. This article has 88 citations and is from a highest quality peer-reviewed journal.
(baba2020emergingrolesof pages 1-2): Takashi Baba and Tamas Balla. Emerging roles of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate as regulators of multiple steps in autophagy. The Journal of Biochemistry, 168(4):329-336, Aug 2020. URL: https://doi.org/10.1093/jb/mvaa089, doi:10.1093/jb/mvaa089. This article has 49 citations.
PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase type 1 beta. Its core
function is phosphorylation of PI4P to PI(4,5)P2/PIP2 at membranes. The original
human PIP5KI study identified PIP5KIbeta as a type I phosphatidylinositol-4-phosphate
5-kinase isoform and notes that PIP5Ks synthesize PI(4,5)P2, a key phosphoinositide
signaling precursor PMID:8955136.
UniProt summarizes the same core activity as PI4P phosphorylation to form PI(4,5)P2
[file:human/PIP5K1B/PIP5K1B-uniprot.txt].
Reactome contains multiple PIP5K1B phosphoinositide reactions. The PI4P to PI(4,5)P2
reaction is the core physiological function. PI, PI3P, and PI(3,4)P2 phosphorylation
entries are useful biochemical/pathway context, but they should not replace the core
PI4P 5-kinase identity.
The Proteostasis Network places PIP5K1B under
Autophagy-Lysosome Pathway|Autophagic lysosome reformation|Regulation of autolysosome membrane composition.
The PN mapping marks this group as no_mapping because the node is a broad taxonomy
container; that means PN membership alone should not be used as evidence. In this
case, however, the primary ALR paper provides a direct starting point: Rong et al.
report that clathrin and PI(4,5)P2 regulate ALR
PMID:22885770,
and the article page identifies Figure 3 as "PIP5K1B is required for the initiation
of ALR" [url:https://www.nature.com/articles/ncb2557].
Because GO appears not to contain a specific "autophagic lysosome reformation" process
term in the local term cache, the most defensible current term is broad
GO:0007040 lysosome organization, with a proposed new ALR-specific child term.
This is not inferred from the PN row alone; it is based on the Rong et al. ALR paper.
GO:0016308 1-phosphatidylinositol-4-phosphate 5-kinase activity as theprotein binding as over-annotated. The uropod paper supports EBP50/ERMGO:0007040 lysosome organization annotation for the ALR context,autophagic lysosome reformation term.Falcon deep research was attempted with just deep-research-falcon human PIP5K1B, but
the provider timed out after 600 seconds and no PIP5K1B-deep-research-falcon.md file
was generated in the gene folder. This review therefore relies on cached GOA/UniProt,
cached publications, Reactome entries, PN mappings, the article page for PMID:22885770,
and these notes.
The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.
*-deep-research*.md file found in this gene directory.ALP|Autophagic lysosome reformation|Regulation of autolysosome membrane composition ; PN-node mapping: group = no_mapping (broad container); class (Autophagic lysosome reformation) = context_only, too_broad_to_propagate β GO:0007040 lysosome organization; branch = no_mapping. No GO projected.This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: O14986
gene_symbol: PIP5K1B
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase type 1 beta, a membrane-associated lipid
kinase whose core function is ATP-dependent phosphorylation of PI4P to generate PI(4,5)P2/PIP2.
PI(4,5)P2 supports membrane signaling, actin remodeling, adhesion, vesicle trafficking, and
autophagic lysosome reformation. Broader WNT/PI3K pathway signaling and uropod localization are
secondary contexts relative to the PI4P 5-kinase/PIP2 biosynthetic role.
alternative_products:
- name: '1'
id: O14986-1
- name: 2 (Isoform 1)
id: O14986-2
sequence_note: VSP_016010, VSP_016011
- name: '3'
id: O14986-3
sequence_note: VSP_054771
existing_annotations:
- term:
id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: PIP5K1B contributes directly to phosphatidylinositol phosphate biosynthesis
by producing PI(4,5)P2 from PI4P.
action: ACCEPT
reason: The process-level term is broad but appropriate for the core PI phosphate
biosynthetic function.
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: PIP5K1B is a cytosolic enzyme that associates with cellular membranes,
including plasma membrane and endomembrane contexts where phosphoinositide
substrates reside. The falcon deep research reinforces the plasma membrane as the
principal site where PIP5K1B generates PI(4,5)P2.
action: ACCEPT
reason: Retain as a supported membrane location for PIP5K1B catalytic activity and
PN-relevant membrane remodeling contexts.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- reference_id: file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
supporting_text: >-
PIP5K1B localizes primarily to the cytoplasmic face of the plasma membrane,
where it carries out its principal function of generating PI(4,5)P2
- term:
id: GO:0012505
label: endomembrane system
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: PIP5K1B is a cytosolic enzyme that associates with cellular membranes,
including plasma membrane and endomembrane contexts where phosphoinositide
substrates reside.
action: ACCEPT
reason: Retain as a supported membrane location for PIP5K1B catalytic activity and
PN-relevant membrane remodeling contexts.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: 'This is the core PIP5K1B molecular function: phosphorylation of PI4P at the
5 position to generate PI(4,5)P2/PIP2. The falcon deep research independently
describes PI4P as the predominant physiological substrate, with PI3P phosphorylation
reported only as an in vitro side activity, consistent with treating the PI3P-using
Reactome side reactions as non-core.'
action: ACCEPT
reason: Retain as the specific catalytic function for this type I PIP5 kinase.
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
supporting_text: PIP5K1B catalyzes the phosphorylation of phosphatidylinositol
4-phosphate (PI4P, PtdIns4P) to generate phosphatidylinositol 4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
supporting_text: PIP5K1B exhibits primary specificity for PI4P as its physiological
substrate
- term:
id: GO:0046488
label: phosphatidylinositol metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: The annotation captures phosphatidylinositol metabolism, but it is broader
than the specific PI phosphate biosynthetic role of PIP5K1B.
action: MODIFY
reason: Replace the broad phosphatidylinositol metabolic/biosynthetic process with
phosphatidylinositol phosphate biosynthetic process.
proposed_replacement_terms:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0051896
label: regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: >-
PI3K/AKT pathway effects are downstream of phosphoinositide metabolism and
are secondary to the direct PIP5K1B lipid kinase function. The falcon deep research
explains the mechanistic basis: PI(4,5)P2 generated by PIP5K1B is the immediate
substrate for class I PI3Ks that produce PI(3,4,5)P3, so any influence on PI3K/AKT
signaling is indirect via product supply rather than a direct regulatory role.
action: KEEP_AS_NON_CORE
reason: Keep as non-core pathway context rather than a defining PIP5K1B process; the
direct gene-level role is PI4P 5-kinase activity and PI phosphate biosynthesis.
proposed_replacement_terms:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
supporting_text: >-
PI(4,5)P2 produced by PIP5K1B serves as the immediate substrate
for class I phosphatidylinositol 3-kinases (PI3Ks), which phosphorylate PI(4,5)P2
at the 3-position to generate phosphatidylinositol 3,4,5-trisphosphate
- term:
id: GO:0052742
label: phosphatidylinositol kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: Phosphatidylinositol kinase activity is true but too general for PIP5K1B,
whose defining activity is PI4P 5-kinase activity.
action: MODIFY
reason: Use the specific 1-phosphatidylinositol-4-phosphate 5-kinase activity term.
proposed_replacement_terms:
- id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0006661
label: phosphatidylinositol biosynthetic process
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1660499
qualifier: involved_in
review:
summary: The annotation captures phosphatidylinositol metabolism, but it is broader
than the specific PI phosphate biosynthetic role of PIP5K1B.
action: MODIFY
reason: Replace the broad phosphatidylinositol metabolic/biosynthetic process with
phosphatidylinositol phosphate biosynthetic process.
proposed_replacement_terms:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0051896
label: regulation of phosphatidylinositol 3-kinase/protein kinase B signal
transduction
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6811558
qualifier: involved_in
review:
summary: PI3K/AKT pathway effects are downstream of phosphoinositide metabolism and
are secondary to the direct PIP5K1B lipid kinase function.
action: KEEP_AS_NON_CORE
reason: Keep as non-core pathway context rather than a defining PIP5K1B process; the
direct gene-level role is PI4P 5-kinase activity and PI phosphate biosynthesis.
proposed_replacement_terms:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
- term:
id: GO:0000285
label: 1-phosphatidylinositol-3-phosphate 5-kinase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676134
qualifier: enables
review:
summary: Reactome assigns this side-reaction/substrate context to PIP5K1B, but it is
not the defining physiological activity. The falcon deep research notes that
PI3P phosphorylation by type I PIP5Ks is observed in vitro, while PI4P remains the
predominant cellular substrate.
action: KEEP_AS_NON_CORE
reason: Keep as non-core biochemical/pathway context and prioritize the PI4P to
PI(4,5)P2 reaction as core.
supported_by:
- reference_id: Reactome:R-HSA-1676134
supporting_text: PIP5K1B
- reference_id: file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
supporting_text: While in vitro studies show that Type I PIP5Ks can also
phosphorylate phosphatidylinositol 3-phosphate (PI3P) to generate PI(3,4)P2 and
PI(3,5)P2, PI4P remains the predominant cellular substrate for PI(4,5)P2 synthesis
- term:
id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676082
qualifier: enables
review:
summary: 'This is the core PIP5K1B molecular function: phosphorylation of PI4P at the
5 position to generate PI(4,5)P2/PIP2.'
action: ACCEPT
reason: Retain as the specific catalytic function for this type I PIP5 kinase.
supported_by:
- reference_id: Reactome:R-HSA-1676082
supporting_text: phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce
phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol
4-phosphate) + ATP = a
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate)
- term:
id: GO:0052810
label: 1-phosphatidylinositol-5-kinase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1675810
qualifier: enables
review:
summary: Reactome assigns this side-reaction/substrate context to PIP5K1B, but it is
not the defining physiological activity.
action: KEEP_AS_NON_CORE
reason: Keep as non-core biochemical/pathway context and prioritize the PI4P to
PI(4,5)P2 reaction as core.
supported_by:
- reference_id: Reactome:R-HSA-1675810
supporting_text: PIP5K1B
- term:
id: GO:0052742
label: phosphatidylinositol kinase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1675773
qualifier: enables
review:
summary: Phosphatidylinositol kinase activity is true but too general for PIP5K1B,
whose defining activity is PI4P 5-kinase activity.
action: MODIFY
reason: Use the specific 1-phosphatidylinositol-4-phosphate 5-kinase activity term.
proposed_replacement_terms:
- id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: enables
review:
summary: 'This is the core PIP5K1B molecular function: phosphorylation of PI4P at the
5 position to generate PI(4,5)P2/PIP2.'
action: ACCEPT
reason: Retain as the specific catalytic function for this type I PIP5 kinase.
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0005886
label: plasma membrane
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: located_in
review:
summary: PIP5K1B is a cytosolic enzyme that associates with cellular membranes,
including plasma membrane and endomembrane contexts where phosphoinositide
substrates reside.
action: ACCEPT
reason: Retain as a supported membrane location for PIP5K1B catalytic activity and
PN-relevant membrane remodeling contexts.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1675773
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1675810
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676082
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676134
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676145
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3772434
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3772436
qualifier: located_in
review:
summary: Cytosol is a correct broad localization for PIP5K1B, but it does not
capture the membrane-associated catalytic biology.
action: KEEP_AS_NON_CORE
reason: Keep as a broad non-core location while emphasizing membrane-associated PI4P
5-kinase activity.
supported_by:
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Cell membrane
- term:
id: GO:0001931
label: uropod
evidence_type: IDA
original_reference_id: PMID:20442317
qualifier: located_in
review:
summary: PIP5KIbeta localizes to the uropod in polarized leukocyte models through an
isoform-specific C-terminal motif.
action: KEEP_AS_NON_CORE
reason: Keep as a supported cell-type-specific localization, not as the core
function.
supported_by:
- reference_id: PMID:20442317
supporting_text: Its final 83 amino acids localize PIP5KIbeta to the uropod of
chemotaxing neutrophils and T cells
- reference_id: PMID:20442317
supporting_text: interact with ezrin-radixin-moesin (ERM) proteins and EBP50
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20442317
qualifier: enables
review:
summary: The interaction evidence is real for uropod targeting, but generic protein
binding is not informative for PIP5K1B function.
action: MARK_AS_OVER_ANNOTATED
reason: Replace generic binding with the mechanistic localization/adaptor context in
narrative rather than retaining GO:0005515 as a reviewed function.
proposed_replacement_terms:
- id: GO:0001931
label: uropod
supported_by:
- reference_id: PMID:20442317
supporting_text: Its final 83 amino acids localize PIP5KIbeta to the uropod of
chemotaxing neutrophils and T cells
- reference_id: PMID:20442317
supporting_text: interact with ezrin-radixin-moesin (ERM) proteins and EBP50
- term:
id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
evidence_type: NAS
original_reference_id: PMID:8955136
qualifier: enables
review:
summary: 'This is the core PIP5K1B molecular function: phosphorylation of PI4P at the
5 position to generate PI(4,5)P2/PIP2.'
action: ACCEPT
reason: Retain as the specific catalytic function for this type I PIP5 kinase.
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
- term:
id: GO:0007040
label: lysosome organization
evidence_type: IMP
original_reference_id: PMID:22885770
qualifier: involved_in
review:
summary: PIP5K1B has direct ALR-context evidence through the PI(4,5)P2 pathway
required for autolysosome tubulation and proto-lysosome budding. GO lacks a
specific ALR term in the local cache, so lysosome organization is the best current
broad term.
action: NEW
reason: Add a broad lysosome organization annotation for the experimentally
supported autophagic lysosome reformation context, with a proposed new
ALR-specific child term to avoid over-broad curation long term.
supported_by:
- reference_id: PMID:22885770
supporting_text: clathrin and phosphatidylinositol-4,5-bisphosphate
(PtdIns(4,5)P(2)) regulate ALR
- reference_id: PMID:22885770
supporting_text: initiation of autolysosome tubulation, and proto-lysosome budding
during ALR
- reference_id: url:https://www.nature.com/articles/ncb2557
supporting_text: PIP5K1B is required for the initiation of ALR
- reference_id: file:human/PIP5K1B/PIP5K1B-notes.md
supporting_text: Figure 3 as "PIP5K1B is required for the initiation of ALR"
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: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: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:20442317
title: An isoform-specific PDZ-binding motif targets type I PIP5 kinase beta to the
uropod and controls polarization of neutrophil-like HL60 cells.
findings: []
- id: PMID:8955136
title: Type I phosphatidylinositol-4-phosphate 5-kinases are distinct members of this
novel lipid kinase family.
findings: []
- id: Reactome:R-HSA-1660499
title: Synthesis of PIPs at the plasma membrane
findings: []
- id: Reactome:R-HSA-1675773
title: PI(3,4)P2 is phosphorylated to PI(3,4,5)P3 by PIP5K1A-C at the plasma membrane
findings: []
- id: Reactome:R-HSA-1675810
title: PI is phosphorylated to PI5P by PIP5K1A/B at the plasma membrane
findings: []
- id: Reactome:R-HSA-1676082
title: PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane
findings: []
- id: Reactome:R-HSA-1676134
title: PI3P is phosphorylated to PI(3,5)P2 by PIP5K1A/B at the plasma membrane
findings: []
- id: Reactome:R-HSA-1676145
title: PI3P is phosphorylated to PI(3,4)P2 by PIP4K2/5K1 at the plasma membrane
findings: []
- id: Reactome:R-HSA-3772434
title: Phosphorylated DVL recruits PIP5K1B to the plasma membrane
findings: []
- id: Reactome:R-HSA-3772436
title: DVL-associated PIP5K1B phosphorylates PI4P to PI(4,5)P2
findings: []
- id: Reactome:R-HSA-6811558
title: PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
findings: []
- id: PMID:22885770
title: Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome
reformation.
findings: []
- id: url:https://www.nature.com/articles/ncb2557
title: 'Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation | Nature Cell Biology'
findings: []
- id: file:human/PIP5K1B/PIP5K1B-deep-research-falcon.md
title: Falcon deep research report for PIP5K1B
findings: []
reference_review:
relevance: MEDIUM
correctness: UNVERIFIED
review_notes: >-
LLM-synthesized (Edison/falcon) report. Cross-checkable, gene-specific claims used
to strengthen this review: PIP5K1B catalyzes PI4P + ATP -> PI(4,5)P2 with PI4P as
the predominant physiological substrate (PI3P phosphorylation in vitro only);
plasma-membrane (cytoplasmic face) as the principal site of PI(4,5)P2 generation;
and PI(4,5)P2 as the immediate class I PI3K substrate that makes PI(3,4,5)P3 (basis
for the indirect, non-core PI3K/AKT annotation). These are consistent with the
cached primary literature (PMID:8955136) and UniProt. The report also asserts a
PIP5Kbeta-specific role at the immunological synapse (CD28/Vav1/filamin A; cites
Kallikourdis et al. 2016, J Immunol) which is genuinely PIP5K1B-specific but is not
currently in GOA and its source paper is not cached, so it was not used to add an
annotation. Many broader functional statements (actin remodeling, adhesion,
endocytosis, cell migration, cancer) are paralog-generalized from PIP5K1A/PIP5K1C
or family-level reviews rather than directly evidenced for PIP5K1B, and the
structural/activation-loop and dimerization mechanisms are described at the
family/PIP5K1A level; these were treated as speculative and not propagated. The
report cites only DOIs (no PMIDs verified against cached publications), hence
UNVERIFIED.
- id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
title: UniProt record for human PIP5K1B
findings: []
- id: file:human/PIP5K1B/PIP5K1B-notes.md
title: PIP5K1B curation notes
findings: []
- id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
title: Proteostasis Network autophagy-lysosome pathway mappings
findings: []
core_functions:
- description: ATP-dependent phosphorylation of phosphatidylinositol 4-phosphate (PI4P)
to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2/PIP2), supporting
phosphoinositide signaling and membrane remodeling.
molecular_function:
id: GO:0016308
label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
directly_involved_in:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
locations:
- id: GO:0005886
label: plasma membrane
- id: GO:0012505
label: endomembrane system
supported_by:
- reference_id: PMID:8955136
supporting_text: Phosphatidylinositol-4-phosphate 5-kinases (PIP5K) synthesize
phosphatidylinositol-4,5-bisphosphate
- reference_id: file:human/PIP5K1B/PIP5K1B-uniprot.txt
supporting_text: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate
(PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate
proposed_new_terms:
- proposed_name: autophagic lysosome reformation
proposed_definition: The process in which nascent lysosomes are regenerated from
autolysosomal membranes following autophagy, including autolysosome tubule
initiation, membrane remodeling, and proto-lysosome budding.
justification: The ALR literature and PN curation need a term more specific than broad
lysosome organization for proteins such as PIP5K1B that regulate autolysosomal
membrane composition and tubulation.
proposed_parent:
id: GO:0007040
label: lysosome organization
supported_by:
- reference_id: PMID:22885770
supporting_text: nascent lysosomes are formed from autolysosomal membranes through
an evolutionarily conserved cellular process, autophagic lysosome reformation
(ALR)
- reference_id: PMID:22885770
supporting_text: initiation of autolysosome tubulation, and proto-lysosome budding
during ALR
suggested_questions:
- question: Should GO add a specific autophagic lysosome reformation term under lysosome
organization, and should PIP5K1B be annotated to that term instead of broad
GO:0007040?
experts:
- Li Yu
- Yongliang Rong
- question: Which PIP5K1B phosphoinositide substrate activities are physiologically
important in vivo versus pathway-level or in vitro side reactions?
experts:
- Richard A. Anderson
- Reactome phosphoinositide curator
suggested_experiments:
- description: Rescue PIP5K1B-depleted cells during starvation-refeeding with wild-type,
kinase-dead, and membrane-targeting mutants while quantifying ALR tubule initiation
and proto-lysosome budding.
experiment_type: genetic rescue/live-cell imaging
hypothesis: PIP5K1B kinase activity and membrane recruitment are required for
PI(4,5)P2-dependent autophagic lysosome reformation.
- description: Measure local PI(4,5)P2 dynamics on autolysosome-derived tubules using
phosphoinositide reporters in cells depleted of PIP5K1B, PIP5K1A, or PIP5K1C.
experiment_type: lipid reporter imaging/RNAi
hypothesis: PIP5K1B supplies a local PI(4,5)P2 pool on ALR membranes that is not fully
redundant with other type I PIP5K isoforms.