O70161 (PI51C_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 115. History...
Names and origin
|Protein names||Recommended name:|
Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma
Short name=PtdIns(4)P-5-kinase 1 gamma
Phosphatidylinositol 4-phosphate 5-kinase type I gamma
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||661 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). PtdIns(4,5)P2 is involved in a variety of cellular processes and is the substrate to form phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), another second messenger. The majority of PtdIns(4,5)P2 is thought to occur via type I phosphatidylinositol 4-phosphate 5-kinases given the abundance of PtdIns4P. Participates in a variety of cellular processes such as vesicle mediated transport, cell adhesion, cell polarization and cell migration. Together with PIP5K1A is required for phagocytosis, but they regulate different types of actin remodeling at sequential steps. Promotes particle attachment by generating the pool of PtdIns(4,5)P2 that induces controlled actin depolymerization to facilitate Fc-gamma-R clustering. Mediates RAC1-dependent reorganization of actin filaments. Required for synaptic vesicle transport. Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis. Plays a role in endocytosis mediated by clathrin and AP-2 (adaptor protein complex 2). Required for clathrin-coated pits assembly at the synapse. Participates in cell junction assembly. Modulates adherens junctions formation by facilitating CDH1 trafficking. Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions. Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins. Required for uropodium formation and retraction of the cell rear during directed migration. Has a role in growth factor- stimulated directional cell migration and adhesion. Required for talin assembly into nascent adhesions forming at the leading edge toward the direction of the growth factor. Negative regulator of T-cell activation and adhesion. Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor. Together with PIP5K1A have a role during embryogenesis and together with PIP5K1B may have a role immediately after birth. Ref.1 Ref.6 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.16 Ref.17 Ref.18
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate = ADP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate.
Activated by phosphatidic acid. Ref.1
Isoform 1 interacts with TLN1. Interacts with TLN2; interaction stimulates lipid kinase activity. May compete with beta-integrins for the same binding site on TLN1 and TLN2. Interacts with ARF6 By similarity. Interacts with AP2B1. Isoform 1 interacts with AP2M1; phosphorylation of PIP5K1C by CSK disrupts the interaction; clathrin competes with PIP5K1C. Interacts with CDH1 By similarity. Interacts with CSK. Interacts with PLCG1; interaction is abolished upon EGF stimulation. Ref.6 Ref.7 Ref.10 Ref.11 Ref.15
Cell membrane; Peripheral membrane protein; Cytoplasmic side. Endomembrane system. Cytoplasm. Cell junction › focal adhesion. Cell junction › adherens junction. Cell projection › ruffle membrane. Cell projection › phagocytic cup. Cell projection › uropodium. Note: During directional migration isoform 1 localized at the uropodium, and isoform 3 localized all along cell membrane including the uropodium and the leading edge. Ref.6 Ref.7 Ref.12 Ref.16 Ref.17
High expression in brain. Also detected in lung, thymus, heart, testicle, kidney and embryo. Highly expressed in forebrain, in particular in cerebellum, hippocampus and cerebral cortex. Ref.1 Ref.8 Ref.17
Expression increases during embryonic development and continued to steadily increase postnatally. Ref.17
Phosphorylation on Ser-645 negatively regulates binding to TLN2 and is strongly stimulated in mitosis. Phosphorylation on Tyr-644 is necessary for targeting to focal adhesions. Phosphorylation on Ser-645 and Tyr-644 are mutually exclusive. Phosphorylated by SYK and CSK. Tyrosine phosphorylation is enhanced by PTK2 signaling. Phosphorylated at Tyr-634 upon EGF stimulation. Some studies suggest that phosphorylation on Tyr-644 enhances binding to tailins (TLN1 and TLN2); others that phosphorylation at Tyr-644 does not directly enhance binding to tailins (TLN1 and TLN2) but may act indirectly by inhibiting phosphorylation at Ser-645. Ref.6 Ref.7 Ref.10 Ref.11 Ref.16
Acetylation at Lys-265 and Lys-268 seems to decrease lipid kinase activity. Deacetylation of these sites by SIRT1 positively regulates the exocytosis of TSH-containing granules from pituitary cells By similarity.
According to some authors, mutants die within hours after birth and are unable to feed after birth (Ref.9). According to another report, mutants are embryonically lethal at organogenesis stage, and display cardiovascular and neuronal defects (Ref.9). PIP5K1C and PIP5K1B double mutant mice die within minutes after birth. PIP5K1C and PIP5K1A double mutant mice are embryonic lethal. Bone marrow-derived macrophages are defective in phagocytosis, attachment to IgG-opsonized particles and Fc-gamma-R clustering, and display highly polymerized actin cytoskeleton. Neurons display defects in synaptic transmission due to defects in synaptic vesicle trafficking at different levels. T-cells mutant for isoform 1 display increase adhesion and polarization. Ref.9 Ref.13 Ref.16 Ref.17 Ref.18
Contains 1 PIPK domain.
KM=37 µM for PtdIns4P
KM=39 µM for ATP
The sequence BAC65601.2 differs from that shown. Reason: Erroneous initiation.
|This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: O70161-1) |
Also known as: PIPKIgamma661;
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: O70161-2) |
Also known as: PIPKIgamma627;
The sequence of this isoform differs from the canonical sequence as follows:
635-635: F → FFAHGRYWLFSPRRRQLRAVTPNHTGT
|Note: No experimental confirmation available.|
|Isoform 3 (identifier: O70161-3) |
Also known as: PIPKIgamma635;
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 661||661||Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma||PRO_0000185463|
|Domain||75 – 443||369||PIPK|
|Region||636 – 661||26||Mediates interaction with TLN2|
Amino acid modifications
|Modified residue||265||1||N6-acetyllysine By similarity|
|Modified residue||268||1||N6-acetyllysine By similarity|
|Modified residue||634||1||Phosphotyrosine; by EGFR Ref.6 Ref.11|
|Modified residue||644||1||Phosphotyrosine; by CSK Ref.6 Ref.7|
|Modified residue||645||1||Phosphoserine; by CDK5, MAPK1 and CDK1 By similarity|
|Alternative sequence||343 – 402||60||Missing in isoform 2.||VSP_016013|
|Alternative sequence||635||1||F → FFAHGRYWLFSPRRRQLRAV TPNHTGT in isoform 2.||VSP_016014|
|Alternative sequence||636 – 661||26||Missing in isoform 3.||VSP_016015|
|Mutagenesis||253||1||D → A: Abolishes lipid kinase activity. Does not affect targeting of TLN1 to plasma membrane. Affects assembly of TLN1 into focal adhesions. Affects uropodium formation and retraction of the cell rear. Ref.6 Ref.12|
|Mutagenesis||634||1||Y → F: Can not rescue the effect PIP5K1C knockdown on EGF-stimulated cell migration. Does not affect lipid kinase activity. Does not alter binding to tailin. Decreased tailin assembly into focal adhesions. Increased interaction with PLCG1. Ref.11|
|Mutagenesis||635||1||F → A: Abolishes interaction with AP2B1. Ref.15|
|Mutagenesis||642||1||W → A: Abolishes interaction with AP2B1. Ref.15|
|Mutagenesis||644||1||Y → F: Loss of phosphorylation by CSK. Abolishes interaction with AP-2 complex. Can not rescue the effect PIP5K1C knockdown on EGF-stimulated cell migration. Ref.7 Ref.10 Ref.11 Ref.15|
|Mutagenesis||645||1||S → F: Can not rescue the effect PIP5K1C knockdown on EGF-stimulated cell migration. Decreased tailin assembly into focal adhesions. Ref.11|
|Mutagenesis||646||1||P → F: Abolishes interaction with AP-2 complex. Ref.10|
|Mutagenesis||647||1||L → V: Abolishes interaction with AP-2 complex. Ref.10|
|Sequence conflict||110||1||V → M in BAA25664. Ref.1|
|Sequence conflict||122||1||L → F in BAA25664. Ref.1|
Helix Strand Turn
|Beta strand||642 – 644||3|
|Helix||646 – 648||3|
|||"Type I phosphatidylinositol-4-phosphate 5-kinases. Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family."|
Ishihara H., Shibasaki Y., Kizuki N., Wada T., Yazaki Y., Asano T., Oka Y.
J. Biol. Chem. 273:8741-8748(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, ENZYME REGULATION, ALTERNATIVE SPLICING, TISSUE SPECIFICITY.
|||"Prediction of the coding sequences of mouse homologues of KIAA gene: II. The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries."|
Okazaki N., Kikuno R., Ohara R., Inamoto S., Aizawa H., Yuasa S., Nakajima D., Nagase T., Ohara O., Koga H.
DNA Res. 10:35-48(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Fetal brain.
|||Okazaki N., Kikuno R., Nagase T., Ohara O., Koga H.|
Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION.
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Strain: C57BL/6J and NOD.
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Tissue: Brain and Kidney.
|||"Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions."|
Ling K., Doughman R.L., Firestone A.J., Bunce M.W., Anderson R.A.
Nature 420:89-93(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN FOCAL ADHESION DYNAMIC, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYROSINE RESIDUES, INTERACTION WITH TLN1, MUTAGENESIS OF ASP-253.
|||"Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch."|
Ling K., Doughman R.L., Iyer V.V., Firestone A.J., Bairstow S.F., Mosher D.F., Schaller M.D., Anderson R.A.
J. Cell Biol. 163:1339-1349(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TLN1, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-644, MUTAGENESIS OF TYR-644.
|||"A novel neuronal-specific splice variant of Type I phosphatidylinositol 4-phosphate 5-kinase isoform gamma."|
Giudici M.-L., Emson P.C., Irvine R.F.
Biochem. J. 379:489-496(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
|||"Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking."|
Di Paolo G., Moskowitz H.S., Gipson K., Wenk M.R., Voronov S., Obayashi M., Flavell R., Fitzsimonds R.M., Ryan T.A., De Camilli P.
Nature 431:415-422(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SYNAPTIC VESICLE TRAFFICKING, DISRUPTION PHENOTYPE.
|||"Type Igamma661 phosphatidylinositol phosphate kinase directly interacts with AP2 and regulates endocytosis."|
Bairstow S.F., Ling K., Su X., Firestone A.J., Carbonara C., Anderson R.A.
J. Biol. Chem. 281:20632-20642(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLATHRIN-MEDIATED ENDOCYTOSIS, INTERACTION WITH AP2M1 AND TLN1, PHOSPHORYLATION, MUTAGENESIS OF TYR-644; PRO-646 AND LEU-647.
|||"Type I gamma phosphatidylinositol phosphate kinase is required for EGF-stimulated directional cell migration."|
Sun Y., Ling K., Wagoner M.P., Anderson R.A.
J. Cell Biol. 178:297-308(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION AND ADHESION, INTERACTION WITH PLCG1, PHOSPHORYLATION AT TYR-634, MUTAGENESIS OF TYR-634; TYR-644 AND SER-645.
|||"Type Igamma PIP kinase is a novel uropod component that regulates rear retraction during neutrophil chemotaxis."|
Lokuta M.A., Senetar M.A., Bennin D.A., Nuzzi P.A., Chan K.T., Ott V.L., Huttenlocher A.
Mol. Biol. Cell 18:5069-5080(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NEUTROPHIL CHEMOTAXIS, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-253.
|||"PIP5KI gamma is required for cardiovascular and neuronal development."|
Wang Y., Lian L., Golden J.A., Morrisey E.E., Abrams C.S.
Proc. Natl. Acad. Sci. U.S.A. 104:11748-11753(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN EMBRYOGENESIS, DISRUPTION PHENOTYPE.
|||"The phagosomal proteome in interferon-gamma-activated macrophages."|
Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"Clathrin regulates the association of PIPKIgamma661 with the AP-2 adaptor beta2 appendage."|
Thieman J.R., Mishra S.K., Ling K., Doray B., Anderson R.A., Traub L.M.
J. Biol. Chem. 284:13924-13939(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AP2B1, MUTAGENESIS OF PHE-635; TRP-642 AND TYR-644.
|||"Essential and unique roles of PIP5K-gamma and -alpha in Fcgamma receptor-mediated phagocytosis."|
Mao Y.S., Yamaga M., Zhu X., Wei Y., Sun H.-Q., Wang J., Yun M., Wang Y., Di Paolo G., Bennett M., Mellman I., Abrams C.S., De Camilli P., Lu C.Y., Yin H.L.
J. Cell Biol. 184:281-296(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHAGOCYTOSIS, SUBCELLULAR LOCATION, PHOSPHORYLATION, DISRUPTION PHENOTYPE.
|||"Phosphatidylinositol-4-phosphate 5-kinases and phosphatidylinositol 4,5-bisphosphate synthesis in the brain."|
Volpicelli-Daley L.A., Lucast L., Gong L.-W., Liu L., Sasaki J., Sasaki T., Abrams C.S., Kanaho Y., De Camilli P.
J. Biol. Chem. 285:28708-28714(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN EMBRYOGENESIS, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE.
|||"PIPKI gamma 90 negatively regulates LFA-1-mediated adhesion and activation in antigen-induced CD4+ T cells."|
Wernimont S.A., Legate K.R., Simonson W.T.N., Fassler R., Huttenlocher A.
J. Immunol. 185:4714-4723(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL ADHESION, DISRUPTION PHENOTYPE.
|||"Structural basis for phosphatidylinositol phosphate kinase type Igamma binding to talin at focal adhesions."|
de Pereda J.M., Wegener K.L., Santelli E., Bate N., Ginsberg M.H., Critchley D.R., Campbell I.D., Liddington R.C.
J. Biol. Chem. 280:8381-8386(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 636-652 IN COMPLEX WITH TLN1.
|+||Additional computationally mapped references.|
|AB006916 mRNA. Translation: BAA25664.1.|
AK122319 mRNA. Translation: BAC65601.2. Different initiation.
AK154816 mRNA. Translation: BAE32849.1.
AK171576 mRNA. Translation: BAE42536.1.
BC019138 mRNA. Translation: AAH19138.1.
BC094665 mRNA. Translation: AAH94665.1.
|RefSeq||NP_001140159.1. NM_001146687.1. [O70161-3]|
NP_032870.2. NM_008844.2. [O70161-1]
3D structure databases
|SMR||O70161. Positions 76-328. |
Protein-protein interaction databases
|IntAct||O70161. 8 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000105327; ENSMUSP00000100964; ENSMUSG00000034902. [O70161-1]|
ENSMUST00000163075; ENSMUSP00000124155; ENSMUSG00000034902. [O70161-3]
|UCSC||uc007ghc.2. mouse. [O70161-1]|
|MGI||MGI:1298224. Pip5k1c. |
Gene expression databases
Family and domain databases
|Gene3D||3.30.800.10. 1 hit. |
3.30.810.10. 1 hit.
|InterPro||IPR023610. PInositol-4-P-5-kinase. |
|PANTHER||PTHR23086. PTHR23086. 1 hit. |
|Pfam||PF01504. PIP5K. 1 hit. |
|SMART||SM00330. PIPKc. 1 hit. |
|PROSITE||PS51455. PIPK. 1 hit. |
|ChiTaRS||PIP5K1C. mouse. |
|Accession||Primary (citable) accession number: O70161|
Secondary accession number(s): Q505A1, Q80TW9, Q8VCU5
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|