O60331 (PI51C_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 116. 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||Homo sapiens (Human) [Reference proteome]|
|Taxonomic identifier||9606 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo|
|Sequence length||668 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.5 Ref.6 Ref.8 Ref.9
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate = ADP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate.
Activated by interaction with TLN2. Ref.5
Interacts with TLN1 By similarity. 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. Interacts with AP2B1. Interacts with AP2M1; phosphorylation of PIP5K1C by CSK disrupts the interaction; clathrin competes with PIP5K1C By similarity. Interacts with CDH1. Interacts with CSK By similarity. Interacts with PLCG1; interaction is abolished upon EGF stimulation By similarity. Ref.5 Ref.6 Ref.8
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: Detected in plasma membrane invaginations. Isoform 3 is detected in intracellular vesicle-like structures. Ref.1 Ref.5 Ref.6 Ref.8
Isoform 1 is strongly expressed in brain and also detected in heart and lung. Isoform 2 is strongly expressed in pancreas and liver and in lesser quantities in brain, heart, lung and kidney. Isoform 3 is detected in large amounts in heart and large intestine, is also present in lung, pancreas and thyroid, and to a lesser extent in brain, stomach and kidney. Ref.1
Phosphorylation on Ser-650 negatively regulates binding to TLN2 and is strongly stimulated in mitosis. Phosphorylation on Tyr-649 is necessary for targeting to focal adhesions. Phosphorylation on Ser-650 and Tyr-649 are mutually exclusive. Phosphorylated by SYK and CSK By similarity. Tyrosine phosphorylation is enhanced by PTK2 signaling. Phosphorylated at Tyr-639 upon EGF stimulation. Some studies suggest that phosphorylation on Tyr-649 enhances binding to tailins (TLN1 and TLN2). According to Ref.7 phosphorylation at Tyr-649 does not directly enhance binding to tailins (TLN1 and TLN2) but may act indirectly by inhibiting phosphorylation at Ser-650. Ref.7
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. Ref.10
|Involvement in disease|
Lethal congenital contracture syndrome 3 (LCCS3) [MIM:611369]: A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non-progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS3 patients present at birth with severe multiple joint contractures and severe muscle wasting and atrophy, mainly in the legs. Death occurs minutes to hours after birth due to respiratory insufficiency. The phenotype can be distinguished from that of LCCS1 by the absence of hydrops, fractures and multiple pterygia, and from LCCS2 by the absence of neurogenic bladder defect.
Contains 1 PIPK domain.
The sequence BAA25515.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.
|This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: O60331-1) |
Also known as: PIPKIgamma-90; PIPKIgamma-668; PIPkinIgamma-a; PIPKIgamma_i2;
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: O60331-2) |
Also known as: variant 700; PIPKIgamma-700; PIPKIgamma_i4;
The sequence of this isoform differs from the canonical sequence as follows:
640-668: FPTDERSWVYSPLHYSAQAPPASDGESDT → FWRLWGPHAP...GAMSCCVSVS
|Isoform 3 (identifier: O60331-3) |
Also known as: variant 707; PIPKIgamma-707; PIPKIgamma_i5;
The sequence of this isoform differs from the canonical sequence as follows:
641-668: PTDERSWVYSPLHYSAQAPPASDGESDT → FTDGRYWIYS...TSVVFQKGFG
|Isoform 4 (identifier: O60331-4) |
Also known as: PIPKIgamma-87; PIPKIgamma-640; PIPkinIgamma-b; PIPKIgamma_i1;
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 – 668||668||Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma||PRO_0000185462|
|Domain||75 – 443||369||PIPK|
|Region||641 – 668||28||Mediates interaction with TLN2|
Amino acid modifications
|Modified residue||265||1||N6-acetyllysine Ref.10|
|Modified residue||268||1||N6-acetyllysine Ref.10|
|Modified residue||639||1||Phosphotyrosine; by EGFR By similarity|
|Modified residue||649||1||Phosphotyrosine; by CSK Ref.7|
|Modified residue||650||1||Phosphoserine; by CDK5, MAPK1 and CDK1 Ref.7|
|Alternative sequence||640 – 668||29||FPTDE…GESDT → FWRLWGPHAPTWPWRREGRA ACLCPYPPHVVTPFPGTGLC ASWSPDGTGGLGAMSCCVSV S in isoform 2.||VSP_042078|
|Alternative sequence||641 – 668||28||PTDER…GESDT → FTDGRYWIYSPRHRRLRAVT LSASGTVSDRSRPPWGEGAV PLGQQGAAGPRPEAQCLTSV VFQKGFG in isoform 3.||VSP_042080|
|Alternative sequence||641 – 668||28||Missing in isoform 4.||VSP_042079|
|Natural variant||253||1||D → N in LCCS3; loss of activity. Ref.12||VAR_036996|
|Mutagenesis||650||1||S → D: Abolishes binding to TLN2. Affects localization to focal adhesions. Ref.7|
|Mutagenesis||650||1||S → N: Does not affect binding to TLN2 and localization to focal adhesions. Ref.7|
|Sequence conflict||236||1||V → M in BAH14283. Ref.3|
Helix Strand Turn
|Helix||644 – 646||3|
|||"Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting."|
Schill N.J., Anderson R.A.
Biochem. J. 422:473-482(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
|||"Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro."|
Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 5:31-39(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
|||"Complete sequencing and characterization of 21,243 full-length human cDNAs."|
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
|||"The DNA sequence and biology of human chromosome 19."|
Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. Lucas S.M.
Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin."|
Di Paolo G., Pellegrini L., Letinic K., Cestra G., Zoncu R., Voronov S., Chang S., Guo J., Wenk M.R., De Camilli P.
Nature 420:85-89(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TLN2, SUBCELLULAR LOCATION, ENZYME REGULATION.
|||"ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Igamma."|
Krauss M., Kinuta M., Wenk M.R., De Camilli P., Takei K., Haucke V.
J. Cell Biol. 162:113-124(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ARF6, SUBCELLULAR LOCATION.
|||"Regulation of the interaction between PIPKI gamma and talin by proline-directed protein kinases."|
Lee S.Y., Voronov S., Letinic K., Nairn A.C., Di Paolo G., De Camilli P.
J. Cell Biol. 168:789-799(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-649 AND SER-650, MUTAGENESIS OF SER-650.
|||"Type I gamma phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with mu 1B adaptin."|
Ling K., Bairstow S.F., Carbonara C., Turbin D.A., Huntsman D.G., Anderson R.A.
J. Cell Biol. 176:343-353(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CDH1.
|||"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.
|||"SIRT1 regulates thyroid-stimulating hormone release by enhancing PIP5Kgamma activity through deacetylation of specific lysine residues in mammals."|
Akieda-Asai S., Zaima N., Ikegami K., Kahyo T., Yao I., Hatanaka T., Iemura S., Sugiyama R., Yokozeki T., Eishi Y., Koike M., Ikeda K., Chiba T., Yamaza H., Shimokawa I., Song S.Y., Matsuno A., Mizutani A. Setou M.
PLoS ONE 5:E11755-E11755(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION AT LYS-265 AND LYS-268, DEACETYLATION BY SIRT1.
|||"PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions."|
van den Bout I., Divecha N.
J. Cell Sci. 122:3837-3850(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinositol pathway."|
Narkis G., Ofir R., Landau D., Manor E., Volokita M., Hershkowitz R., Elbedour K., Birk O.S.
Am. J. Hum. Genet. 81:530-539(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LCCS3 ASN-253, CHARACTERIZATION OF VARIANT LCCS3 ASN-253.
|+||Additional computationally mapped references.|
|FJ965536 mRNA. Translation: ACS73483.1.|
FJ965537 mRNA. Translation: ACS73484.1.
AB011161 mRNA. Translation: BAA25515.1. Different initiation.
AK315912 mRNA. Translation: BAH14283.1.
AC005542 Genomic DNA. Translation: AAC32904.1.
AC093071 Genomic DNA. No translation available.
AC004637 Genomic DNA. No translation available.
|RefSeq||NP_001182662.1. NM_001195733.1. [O60331-4]|
NP_036530.1. NM_012398.2. [O60331-1]
XP_005259580.1. XM_005259523.2. [O60331-3]
3D structure databases
|SMR||O60331. Positions 76-328. |
Protein-protein interaction databases
|BioGrid||116969. 6 interactions.|
|IntAct||O60331. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000335312; ENSP00000335333; ENSG00000186111. [O60331-1]|
ENST00000537021; ENSP00000444779; ENSG00000186111. [O60331-2]
ENST00000539785; ENSP00000445992; ENSG00000186111. [O60331-4]
ENST00000589578; ENSP00000466363; ENSG00000186111. [O60331-3]
|UCSC||uc002lyj.2. human. [O60331-1]|
uc010xhr.2. human. [O60331-3]
|HGNC||HGNC:8996. PIP5K1C. |
|MIM||606102. gene. |
|Orphanet||137783. Lethal congenital contracture syndrome type 3. |
Enzyme and pathway databases
|Reactome||REACT_111045. Developmental Biology. |
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. human. |
|Accession||Primary (citable) accession number: O60331|
Secondary accession number(s): B7Z9E7 Q7LE07
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
|Disclaimer||Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.|
Index of protein domains and families
Index of Protein Data Bank (PDB) cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
|Human polymorphisms and disease mutations|
Index of human polymorphisms and disease mutations
|Human entries with polymorphisms or disease mutations|
List of human entries with polymorphisms or disease mutations
|Human chromosome 19|
Human chromosome 19: entries, gene names and cross-references to MIM