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FLASH GENE

Symbol

PIK3CA

contributors: mct/npt/pgu - updated : 06-07-2015

HGNC name	phosphoinositide-3-kinase, catalytic, alpha polypeptide
HGNC id	8975

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CLOVES congenital lipomatous overgrowth, vascular malformations, and epidermal nevi syndrome CWS5 Cowden syndrome 5 MCAP megalencephaly-capillary malformation-polymicrogyria syndrome
Location	3q26.32      Physical location : 178.866.310 - 178.952.495
Synonym name	PI3-kinase p110 subunit alpha
	phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, alpha isoform
	PtdIns-3-kinase p110
Synonym symbol(s)	PI3K, p110-alpha, MGC142161, MGC142163, CLOVE, MCAP, MCM, MCMTC
EC.number	2.7.1.137, 2.7.1.153

DNA

TYPE	functioning gene
STRUCTURE	86.18 kb     21 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	promoter transcriptionally silenced by the tumor suppressor protein TP53

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006218 21 - 3724 NP_006209 124.3 1068 - 1994 7713498

EXPRESSION

Type

widely

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 Digestive liver       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol   bone marrow     highly Homo sapiens Connective bone     predominantly Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal adaptor binding domain (ABD)
	a phosphotyrosine binding domain (PTB),
	the p85 binding domain
	a helical domain
	a potential RAS-binding domain(RBD)
	a membrane-binding C2 domain

mono polymer

heteromer , dimer

HOMOLOGY

Homologene

FAMILY

PI3/PI4-kinase family

CATEGORY

enzyme , receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic

basic FUNCTION	activating Akts in the antiapoptotic PIK3 pathway
	regulator of cell growth and apoptosis
	mediating angiogenesis and expression of VEGF in endothelial cells
	function as an oncogene among anaplastic thyroid carcinomas and less frequently well-differentiated thyroid carcinomas
	with PIK3CB, regulate S-phase entry
	mediate oncogenic signalling induced by several oncogenes such as ERRB2 or RAS
	plays a key role in insulin action and tumorigenesis
	positively regulates the development and function of both osteoblasts and osteoclasts
	critical for myofiber maturation and Z-disc alignment
	regulates the expression of genes essential for cardiac structure and Z-disc signaling
	is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes
	PIK3CA/AKT1, may be involved in the response to hypoxia of immature and, more specifically, of mature dendritic cells to sustain their trafficking and functions within hypoxic microenvironments

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

	PIK3CA/AKT1/MTOR signaling pathway, which was overactivated in aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism (IHA)compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of primary aldosteronism (PA)
	central role of PI3K/AKT signaling in vascular, limb and brain development
	signaling pathway that controls angiogenesis immediately downstream of PIK3CA through ARAP3 to the RHO and ARF family of small GTPases

a component

heterodimerizing with p85 subunit

INTERACTION

DNA

RNA

small molecule

protein	activating AKTs in the antiapoptotic PIK3 pathway
	mediating angiogenesis and expression of VGEF in endothelial cells
	regulates CACNA1C in cardiac myocytes
	interacts with melusin (ITGB1BP2), and is critical for Z-disc alignment
	key role of class I PIK3CA in IL2RA endocytosis that creates a link with IL2 signalling
	RAB39A interacts with PIK3CA and the AAs from 34(th) to 41(st) in RAB39A were indispensable for this interaction
	FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PIK3CA-AKT1 signaling pathway by way of a Ca(2+) /CALM1-dependent mechanism
	CREG1 is a novel factor in regulating endothelial differentiation and vasculogenesis via VEGFA/PIK3CA/AKT1 pathway
	functional RAS interaction with PIK3CA in host tissue is required for the establishment of a growth-permissive environment for the tumor, particularly for tumor-induced angiogenesis
	PIK3CA signalling prevents NUAK1-dependent phosphorylation of PPP1R12A protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility

cell & other

REGULATION

activated by

growth factors,through binding p85 adaptor proteins (PIK3R1,PIK3R2,PIK3R3)

induced by

the oncogenic transcription factor Y-box binding protein-1 (YBX1)

Other

antagonized by PTEN,

ASSOCIATED DISORDERS

corresponding disease(s)

CLOVES , MCAP , CWS5

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in head and necks squamous cell carcinomas tumoral       gain of function in colorectal cancer and glioblastoma tumoral somatic mutation       in anaplastic oligodendrogliomas, in anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas tumoral somatic mutation       in breast carcinomas and hepatocellular carcinomas, modulate PI3K signalling to influence tumour behaviour and occur in up to 40p100 of breast cancers tumoral somatic mutation       in colorectal and gastric carcinomas tumoral   amplification     in thyroid carcinoma, relatively common and may be a novel mechanism in activating the PI3K/Akt pathway in some thyroid tumors tumoral somatic mutation       in epidermal nevi (EN) in seborrheic keratoses (SK)in association to mutations in FGFR3 tumoral somatic mutation       are likely to occur late in the development of oral squamous cell carcinoma, and play a crucial role through the PI3K-AKT signaling pathway in cancer progression tumoral       gain of function in diffuse large B cell lymphoma constitutional somatic mutation       somatic mosaicism for postzygotic activating mutations in the PIK3CA gene constitutional somatic mutation     gain of function in Cowden and Cowden-like syndrome constitutional somatic mutation     gain of function in isolated congenital macrodactyly is caused by somatic activation of the PI3K/AKT cell-signaling pathway and is genetically and biochemically related to other overgrowth syndromes constitutional       gain of function of PIK3CA/AKT1/MTOR axis in individuals with Down syndrome, with and without AD pathology, in comparison with respective controls constitutional somatic mutation       cause 54p100 of venous malformation

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer brain   therapeutic target in anaplastic oligodendrogliomas, in anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas osteoarticular bone   therapeutic agents that target this enzyme have the potential to significantly affect bone homeostasis cancer thyroid   targeting in the treatment of anaplastic thyroid carcinomas tumor vascular   inhibitors of PIK3Ca might have therapeutic applications for individuals with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations in PIK3CA cancer     targeting the interaction of RAS with PIK3CA has the potential to impair tumor formation by altering the tumor-host relationship, in addition to previously described tumor cell-autonomous effects

ANIMAL & CELL MODELS