|p85alpha||PIK3R1, GRB1, PI13K|
|Molecule Type||Antigen Expression||Molecular Weight|
Min / Max
|Non-lineage Restricted Molecule|
|p85a is ubiquitously expressed in human tissues and on cell lines. p55a expression is highest in the skeletal muscle and brain. p50a expression is highest in the liver and kidney. The location of p85a is primarily cytosolic in quiescent cells but a portion is found associated with cellular membranes following cell stimulation with various agents. |
| MOLECULAR FAMILY NAME: class IA P13Ks -->class I P13K regulatory/adaptor subunits --> pi3-K regulatory subunits.|
p85a names: phosphatidylinsitol 3-kinase regulatory 85-kDa a [p85a, pi3-k regulatory subunit a p85, phosphatidylinositol 3-kinase-associated p85-a , GRB1, phosphoinositide-3-kinase regulatory subunit polypeptide 1 (phosphatidylinositol 3-kinase regulatory, 1, phosphatidylinositol 3-OH kinase), ptdins-3-kinase p85-a (Ptdlns-3-kinase, P13-K, P13K), 85kDa regulatory (85kDa adaptor), p50a, and p55a.
p85a is a regulatory or adaptor subunit of class IA phosphoinositide 3-kinases (P13K). p85a is comprised of several modular domains that mediate interaction with other signaling proteins. p85a has, in the order from the N-terminus a SH3 domain, a 1st proline-rich motif, a RhoGAP-like domain with a region of homology to Rho GTPase-activating proteins, a 2nd proline-rich motif, a 1st SH2 domain (N-SH2), a coiled-coil domain that interacts with the catalytic subunit, and a 2nd SH2 domain (C-SH2).
P85a usually migrates as a single band by SDS-PAGE, slightly faster than the p85b isoform. p55a and p50a may migrate as doublets, perhaps because of alternative splicing of the 24bp exon.
There are 3 main variants, p85a, p55a and p50a, which are probably generated by alternative splicing. Another set of splice variants can be generated by inclusion of 24bp with an 8 aa exon near the 3' end. It is possible that the 3 main variants, which have different start codons, are generated by alternative promoter usage.
p85a and its variants are not highly phosphorylated. Tyrosine phosphorylation may occur but does not appear to activate the enzyme complex. There is some evidence for a negative regulatory role. It is important to note that increased P13K activity in phosphotyrosine immuno-precipitates after cellular activation is probably not the result of direct activation of P13K by tyrosine phosphorylation. Rather, this phenomenon results from the association of P13K with tyrosine phosphorylated proteins, which are more abundant following many stimulation protocols. Serine phosphorylation at residue 608 is carried out by the P13K catalytic subunit p100a, which has intrinsic protein kinase activity in addition to its well-known lipid kinase activity. Phosphorylation of Ser608 reduces enzyme activity and is thought to represent an auto-shutoff mechanism. No evidence has been presented thusfar that this mechanism is also operative in vivo.
|LIGANDS AND MOLECULES ASSOCIATED WITH p85a|
|p85a and its splice variants form heterodimers with the class IA P13Ks p110a, p110b and p110d. The stability of the catalytic subunits, p110a, p110b and p110d, is increased by association with p85a. p85a associates with numberous other signaling proteins via its modular domains. These interactions often bring the associated p110 catalytic subunit into proximity with its substrates in cellular membranes. Binding of both Src homology-2 (SH2) domains of p85a to tyrosine-phosphorylated sequences increases the intrinsic kinase activity of the catalytic subunit. In summary, p85a and other regulatory subunits can regulate both the subcellular location and enzymatic activity of the P13K heterodimer.|
p85a is not an enzyme but associates constitutively with class IA phosphoinositide 3-kinase, enzmes which phosphorylate the 3'-hydroxyl on phosphatidylinositol (PtIns), PtdIns-4-phosphate, PtdIns-5-phosphate and PtdIns-4,5-bisphosphate.
DISEASE RELEVANCE AND FUNCTION OF p85a IN INTACT ANIMAL
The human p85a gene has not been clearly implicated in any inherited diseases. Disruption of the p85a gene in knockout mice has revealed important functions in the intact animal. Knockout mice lacking all known variants die in the first week of life, probably from liver degeneration. A small number of knockout mice live for a few weeks but these are hypoglycemic. p85a-/p55a+/p50a+ knockout mice are viable but are hypoglycemic and more insulin sensitive and these knockout mice have a B cell immunodeficiency, as do chimeric mice whose lymphocytes lack all p85a variants.
|MOLECULAR INTERACTIONS -|
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF p85a : No information.
see Biochemical activity.
ENZYMES WHICH MODIFY p85a
see Post-translational modification.
The p85a gene encodes several transcripts derived by alternative splicing and/or alternative promoter usage. There are 2 of these which encode smaller proteins called p55 a and p50.
Database accession numbers
Revised June 25, 2008