InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: INPPL1

Summary

InnateDB Protein

IDBP-588776.3

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

INPPL1

Protein Name

inositol polyphosphate phosphatase-like 1

Synonyms

OPSMD; SHIP2;

Species

Homo sapiens

Ensembl Protein

ENSP00000446360

InnateDB Gene

IDBG-63291 (INPPL1)

Protein Structure

UniProt Annotation

Function

Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol- 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification. {ECO:0000269PubMed:11349134, ECO:0000269PubMed:11739414, ECO:0000269PubMed:12235291, ECO:0000269PubMed:12676785, ECO:0000269PubMed:12690104, ECO:0000269PubMed:15668240, ECO:0000269PubMed:17135240, ECO:0000269PubMed:23273569, ECO:0000269PubMed:9660833}.

Subcellular Localization

Cytoplasm, cytosol. Cytoplasm, cytoskeleton. Membrane; Peripheral membrane protein. Cell projection, filopodium. Cell projection, lamellipodium. Note=Translocates to membrane ruffles when activated, translocation is probably due to different mechanisms depending on the stimulus and cell type. Partly translocated via its SH2 domain which mediates interaction with tyrosine phosphorylated receptors such as the FC-gamma-RIIB receptor (FCGR2B). Tyrosine phosphorylation may also participate in membrane localization. Insulin specifically stimulates its redistribution from the cytosol to the plasma membrane. Recruited to the membrane following M-CSF stimulation. In activated spreading platelets, localizes with actin at filopodia, lamellipodia and the central actin ring.

Disease Associations

Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269PubMed:12086927, ECO:0000269PubMed:15687335}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.Note=Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent. {ECO:0000269PubMed:15220217, ECO:0000269PubMed:17557929}.Opsismodysplasia (OPSMD) [MIM:258480]: A rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with very delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges. {ECO:0000269PubMed:23273569}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Widely expressed, most prominently in skeletal muscle, heart and brain. Present in platelets. Expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes. {ECO:0000269PubMed:12676785, ECO:0000269PubMed:12690104, ECO:0000269PubMed:8530088, ECO:0000269PubMed:9367831, ECO:0000269PubMed:9660833}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 93 experimentally validated interaction(s) in this database.
They are also associated with 4 interaction(s) predicted by orthology.

Experimentally validated
Total	93 [view]
Protein-Protein	93 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	4 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003779	actin binding
GO:0005515	protein binding
GO:0016787	hydrolase activity
GO:0017124	SH3 domain binding
GO:0042169	SH2 domain binding

Biological Process

GO:0001958	endochondral ossification
GO:0002376	immune system process
GO:0006644	phospholipid metabolic process
GO:0006661	phosphatidylinositol biosynthetic process
GO:0006897	endocytosis
GO:0007015	actin filament organization
GO:0007155	cell adhesion
GO:0043647	inositol phosphate metabolic process
GO:0044281	small molecule metabolic process
GO:0046856	phosphatidylinositol dephosphorylation