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FLASH GENE

Symbol

PIK3R1

contributors: mct - updated : 06-09-2017

HGNC name	phosphoinositide-3-kinase, regulatory subunit, polypeptide 1 (p85 alpha)
HGNC id	8979

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	AGM7 agammaglobulinemia 7, autosomal recessive IMD36 Immunodeficiency 36 SHORT SHORT syndrome
Location	5q13.1      Physical location : 67.522.461 - 67.597.647
Synonym name	phosphatidylinositol 3-kinase-associated p-85 alpha
Synonym symbol(s)	PI3KA, GRB1, p85-ALPHA, AGM7, IMD36, p85
EC.number	2.7.1.-

DNA

TYPE	functioning gene
STRUCTURE	86.08 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	with three alternatively spliced isoforms : p85 alpha, p55 alpha and p50 alpha (Inukai)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_181523 16 - 6991 NP_852664 85 724 - 2005 16166093 p85 alpha NM_181504 10 - 5691 NP_852556 55 454 - 2005 16166093 p55 alpha NM_181524 10 - 5823 NP_852665 50 424 - 2005 16166093 p50 alpha NM_001242466 9 - 5554 NP_001229395 - 361 - 2005 16166093

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Lymphoid/Immune spleen       highly Nervous nerve       highly Reproductive female system uterus     highly

cells

System Cell Pubmed Species Stage Rna symbol   adipocyte Lymphoid/Immune B cell Lymphoid/Immune T cell

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal SH3,
	a Rho-GAP domain
	two SH2 domains (nSH2 and cSH2)
	a region of homology to the C terminal region of BCR
	a compact beta-barrel fold very similar to that of PIK3R2 but the ligand-binding specificity differs slightly between the SH3 domains of PIK3R1 and PIK3R2, despite their high structural similarity

HOMOLOGY

Homologene

FAMILY

CATEGORY

enzyme , receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus

basic FUNCTION	acting as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane
	required for insulin-stimulated increase in glucose uptake and glycogen synthesis
	PIK3R1, PIK3R2 modulate PI 3-kinase-dependent signaling by multiple mechanisms and transmit signals independent of PI 3-kinase activation
	is likely a determining factor in ICOS-mediated PI3K activity in T cells
	PIK3R1 and PIK3CB are essential for androgen-stimulated androgen receptor transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression
	critical regulators of various cellular process including cell survival, growth, proliferation, and motility
	PIK3R1 regulatory isoform has partially overlapping functions with PIK3R1 in B cells as well as a unique role in opposing BCR responses
	plays an important role in regulating many cellular processes including cell growth, survival, proliferation, and motility
	its expression plays a critical role in mediating adipose tissue (AT) insulin sensitivity, suggesting that reduced PIK3R1 activity is a key step in the initiation and propagation of the inflammatory response in obese AT
	is a highly dynamic molecule whose conformational flexibility allows it to transiently associate with multiple binding proteins
	novel role of PIK3R1 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of glucocorticoids

CELLULAR PROCESS	cell life, differentiation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

adipocyte differentiation

a component	interacting with inositol polyphosphatase 4-phosphatase and inositol polyphosphatase 5-phosphatase forming complex with SHIP (INPP5D) and SHP2 (PTPN11)
	heterodimer of a p110 catalytic subunit and a p85 regulatory subunit

INTERACTION

DNA

RNA

small molecule

protein	binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain)
	interacting with tyrosine kinase (signal transduction)
	interacting with IRS1 and playing a potential role in glucose homeostasis
	COASY is involved in signaling events in the cell and forms a functional complex with PIK3R1
	directly interacting with the estrogen receptor alpha
	CMIP interacts with the PIK3R1, PIK3R2 and inactivates LCK, which results in Erk1/2 and MAPK14 activation
	regulatory subunits PIK3R1, PIK3R2, interact with XBP1 and increase its nuclear translocation
	CBL ubiquitination of PIK3R1 is essential for EPO-induced EPOR endocytosis
	is a glucocorticoid receptor target gene

cell & other

REGULATION

Phosphorylated by

PRKD1 (mediates phosphorylation of S652 in the C-terminal SH2 domain)

ASSOCIATED DISORDERS

corresponding disease(s)

SHORT , IMD36 , AGM7

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding tumoral germinal mutation     loss of function inactivating mutations in TSC2 and PIK3R1 in urothelial carcinoma tumoral somatic mutation       in endometrioid endometrial cancers (EEC) tumoral     --low   in prostate, lung, ovarian, bladder, and liver cancers, consistent with the possibility that PIK3R1 has tumor suppressor properties tumoral     --low   significantly decreased in primary in renal cell carcinoma (RCC), which promotes propagation, migration, EMT and stem-like phenotype in renal cancer cells, and may contribute to progression and metastasis of RCC tumoral somatic mutation       in glioblastoma (GBM)

Susceptibility

to diabetes with insulin resistance in healthy women of normal weight

Variant & Polymorphism SNP	Met326Ile variant modifying insulin action

Candidate gene
Marker
Therapy target	potential role for reducing p85alpha as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle
	System Type Disorder Pubmed cancer reproductive breast therapeutic target for breast cancer therapy diabete     modulation of PIK3R1 can protect pancreatic beta-cells from ER stress, pointing to a potentially therapeutic target in diabetic states

ANIMAL & CELL MODELS