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Gene Section
Review
PIK3R1 (phosphoinositide-3-kinase, regulatory
subunit 1 (alpha))
Daphne W Bell
National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health,
Bethesda, MD, USA (DWB)
Published in Atlas Database: May 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/PIK3R1ID41717ch5q13.html
DOI: 10.4267/2042/48357
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Co-crystal structures have been reported for the p85αniSH2 domain (residues 322-600) in complex with
p110α (Huang et al., 1997), and for the human p85αiSH2 domain in complex with the bovine p110α-ABD
domain (Miled et al., 2007).
Identity
Other names: GRB1, p85, p85-ALPHA
HGNC (Hugo): PIK3R1
Location: 5q13.1
Description
DNA/RNA
Isoforms: PIK3R1 encodes four distinct protein
isoforms (CCDS3993 (p85α), CCDS3994 (p55α),
CCDS3995 (p50α), and CCDS56374) as a result of
alternative splicing (Inukai et al., 1997).
p85α: p85α has an SH3 domain, a BCR-homology
(BH) domain, and nSH2, iSH2, and cSH2 domains.
The SH3 domain of p85α mediates binding to FAK,
CAS, Apoptin, Ruk, SNX9, Dynamin, Cbl, and BCRABL (reviewed in Mellor et al., 2012).
The BH domain of p85α mediates binding to XB-1,
Rac, Cdc42, Rab5, PTEN (reviewed in Mellor et al.,
2012).
The nSH2 domain of p85α interacts with the helical
domain of p110α (Miled et al., 2007).
The iSH2 domain of p85α interacts with both the ABD
and C2 domains of p110α leading, respectively, to
stabilization and inhibition of p110α (Dhand et al.,
1994; Fu et al., 2004; Elis et al., 2006; Huang et al.,
2007).
Residues D560 and N564 in the p85α-iSH2 domain are
within hydrogen bonding distance of residue N345 of
the p110α-C2 domain (Huang et al., 2007). This
interaction is required for the inhibition of p110α (Wu
et al., 2009).
It has been suggested that residues 447-561 within the
iSH2 might form contact with the plasma membrane
(Huang et al., 2007).
Description
The human PIK3R1 gene encompasses 86102 bp of
DNA and contains 16 exons.
Transcription
Human PIK3R1 is alternatively spliced, resulting in
four major protein-encoding transcripts.
Transcript variant 1: 7011 bp in length; the openreading frame of the coding sequence is 2175 bp.
Transcript variant 2: 2439 bp in length; the openreading frame of the coding sequence is 1365 bp.
Transcript variant 3: 2625 bp in length; the openreading frame of the coding sequence is 1275 bp.
Transcript variant 4: 2473 bp in length; the openreading frame of the coding sequence is 1086 bp.
Pseudogene
None known.
Protein
Note
Crystal structures have been reported for the p85α-SH3
domain (Liang et al., 1996), the p85α-BH domain
(Musacchio et al., 1996), the nSH2 domain (Nolte et
al., 1996), and the p85α-cSH2 domain (Hoedemaeker
et al., 1999).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
876
PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))
Bell DW
(a) Schematic representation of the genomic organization of human PIK3R1. Exons are depicted as boxes. The length (bp) of introns and
exons is shown (top and bottom respectively). (b) PIK3R1 undergoes alternative splicing to produce four major transcript variants. The
exons that comprise each transcript are indicated, relative to the genomic organization illustrated in panel (a).
Domain structure of four protein isoforms encoded by alternative splicing of PIK3R1. Abbreviations: SH3 domain, SRC homology 3
domain; BH domain, breakpoint cluster region homology-domain; nSH2, N-terminal SRC homology 2 domain; iSH2, inter- SRC homology
2 domain; c-SH2, C-terminal SRC homology 2 domain. Proline-rich regions separate the SH3 and BH domains, as well as the BH and
nSH2 domains.
The nSH2 and cSH2 domains of p85α mediate binding
to phosphotyrosine residues in certain receptor tyrosine
kinase and adaptor proteins, in the context of a
pYXXM motif.
p55α: Has a unique amino terminal region of 34 amino
acids. Compared to p85α, p55α lacks the amino
terminal SH3 and BH domains but shares the Cterminal nSH2, iSH2, and cSH2 domains (Inuki et al.,
1997).
p50α: Has a unique amino terminal region of 6 amino
acids. Compared to p85α, p50α lacks the amino
terminal SH3 and BH domains but shares the Cterminal nSH2, iSH2, and cSH2 domains (Inuki et al.,
1997).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
Isoform-4: The shortest isoform. Lacks the first 398
amino acids of p85α but is identical to p85α throughout
the remainder of the protein.
Expression
In mammalian tissues, p85α is expressed in brain, liver,
muscle, fat, kidney, and spleen; p55α is expressed
predominantly in brain and skeletal muscle; and p50α
is expressed in brain, liver, and kidney (Antonetti et al.,
1996; Inuki et al., 1996; Inuki et al.,1997; Geering et
al., 2007).
Localisation
Intracellular; plasma membrane; cytoplasm.
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PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))
Bell DW
(Mauvais-Jarvis et al., 2002; Brachmann et al., 2005;
Taniguchi et al., 2006; Taniguchi et al., 2010; Chagpar
et al., 2010).
Receptor trafficking: p85α has GAP (GTP-ase
Activating Protein) activity towards the Rab4, Rab5,
Rac1, and Cdc42 small GTPases and, to a lesser extent,
towards the Rab6 GTPase. The GAP activity of p85α
resides within the BH domain. Within the BH domain,
Arg151 and Arg274 are important for maximal GAP
activity of p85α. The regulation of Rab4 and Rab5
activity by p85α has been implicated in the endosomal
trafficking of activated PDGFR; cells expressing a
synthetic mutant (p85α-Arg274A) exhibited delayed
degradation of activated PDGFR, prolonged activation
of the MAPK and AKT signalling pathways, and the
capacity to transform NIH 3T3 cells (Chamberlain et
al., 2004; Chamberlain et al., 2008; Chamberlain et al.,
2010).
Regulation of the unfolded protein response: p85α
interacts with XBP-1s, a transcription factor that
regulates the unfolded protein response following
endoplasmic reticulum stress, and facilitates the
relocation of XBP-1s to the nucleus (Park et al., 2010a;
Winnay et al., 2010).
p55α and p50α isoforms: Involved in insulin signaling
(Inuki et al., 1997; Chen et al., 2004).
Function
Regulation of PI3K signaling by p85α: p85α is the
regulatory subunit of PI3K. In quiescent cells, p85α
binds to p110α, the catalytic subunit of PI3K, and both
stabilizes p110α and inhibits the basal activity of
p110α. Ligand-induced phosphorylation of receptor
tyrosine kinases or adaptor proteins on tyrosine
residues, within a pYXXM motif, facilitates the
binding of p85α to the phosphotyrosine residues via its
SH2 domains. Consequently, the inhibitory effect of
p85α on p110α is relieved and PI3K is brought into the
vicinity of the plasma membrane where it catalyzes the
conversion of phosphatidylinositol-4,5-bisphosphate
(PIP2) to phosphatidylinositol-3,4,5-trisphosphate
(PIP3). PIP3 in turn recruits the AKT (v-akt murine
thymoma viral oncogene homolog) serine-threonine
kinase and the PDK1 (phosphoinositide-dependent
protein kinase 1) kinase to the plasma membrane, thus
facilitating the phosphorylation and activation of AKT.
Once activated, AKT can initiate several downstream
signal transduction cascades that regulate protein
synthesis, cell survival, cell growth and metabolism,
and the cell cycle (Reviewed in Vanhaesebroeck et al.,
2010).
Under conditions of nutrient deprivation, p85α is
phosphorylated by IKK on serine-690. Consequently,
the ability of p85α to bind phosphotyrosine proteins is
reduced and PI3K-AKT signaling is diminished (Comb
et al., 2012). Similarly, the activation of PKC family
members by phorbol ester stimulation results in
phosphorylation of p85α on serine-361 and serine-652,
and leads to reduced binding of p85α to
phosphotyrosines and inhibition of PI3K-AKT
signaling (Lee et al., 2011).
Regulation of PTEN by p85α: The PI3K-AKT signal
transduction pathway is antagonized by the activity of
the PTEN phosphatase, which dephosphorylates PIP3
to generate PIP2. Chagpar et al., (2010) demonstrated
that p85α binds directly to PTEN via the p85α-SH3-BH
domains. Cells expressing a synthetic mutant of p85α
that abolished the p85α-PTEN interaction exhibited
increased AKT activation following stimulation by
growth factors. Chagpar et al., thus proposed that p85α
can bind to PTEN and enhance PTEN activity.
Subsequently, Cheung et al., (2011) demonstrated that
compared to wildtype p85α, a tumor-associated mutant
(p85α-E160X) that introduces a premature stop codon
within the BH domain, was associated with reduced
stability of the PTEN protein.
Treatment of cells expressing the p85α-E160X mutant
with a proteosome inhibitor lead to a modest increase
in PTEN levels, further suggesting that the p85α-PTEN
interaction prevents proteosomal degradation of PTEN
and thus increases PTEN stability. The regulation of
PTEN activity by p85α accounts for the increased
insulin sensitivity observed in PIK3R1-/- or p85α-/-mice
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
Homology
Homologues of H. sapiens PIK3R1 exist in P.
troglodytes (99.9% amino acid identity), M. mulatta
(99.2% amino acid identity), C. lupus (95.7% amino
acid identity), B. taurus (96.8% amino acid identity),
M. musculus (96.0% amino acid identity), R.
norvegicus (94.2% amino acid identity), G. gallus
(89.1% amino acid identity), D. rerio (79.3% amino
acid identity), and C. elegans (33.8% amino acid
identity).
Mutations
Note
A polymorphic variant of PIK3R1 (Met326Ile;
rs3730089), has been described (Baier et al., 1998;
Almind et al., 2002).
The PIK3R1-Ile326 allele has been reported to be
associated with increased risk to colon cancer in a
population based case-control study (Li et al., 2008).
Germinal
A germline mutation in exon 6 of PIK3R1 has been
described in a patient with agammaglobulinemia and an
absence of B lineage cells (Conley et al., 2012).
The mutation (p85α-W298X) resulted in loss of p85α
expression, but did not affect p55α or p50α. The patient
was homozygous for the mutation; her parents were
both heterozygous carriers.
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PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))
Bell DW
Distribution of somatic mutations in PIK3R1 relative to the functional domains of p85α. Mutation data are displayed by cancer site, and
were obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC v59 release, May 23rd 2012) (Forbes et al., 2010). Each
square represents a single mutation. Nonsense mutations and frameshift mutations (pink squares) are distinguished from missense
mutations (turquoise squares) and in-frame insertions/deletions (green squares).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
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PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))
Bell DW
independent growth of BaF3 cells (Jaiswal et al., 2009).
Similarily, Cheung et al., showed that the p85α-R574fs,
p85α-T576del, p85α-E160X, p85α-R348X, and p85αR503W mutants induced IL3-independent growth of
BaF3 cells (Cheung et al., 2011).
- Altered p110α-binding: Truncating mutants of p85α
that lack all or part of the the iSH2 domain (p85αE160X, p85α-R162X, p85α-L380fs, p85α-R348X,
p85α-K511VfsX2) fail to bind to p110α (Jaiswal et al.,
2009; Cheung et al., 2011; Urick et al., 2011). In
contrast, small in-frame deletions or missense
mutations within the iSH2 domain retained the ability
to bind p110α (Jaiswal et al., 2009; Cheung et al.,
2011; Urick et al., 2011).
- Increased PI3K activity: Jaiswal et al., (2009)
showed that p85α mutants that were capable of binding
p110α were able to stabilize p110α. p85α/p110α
holoenzymes composed of the p85α-N564 or p85αQYL579delL mutants had increased lipid kinase
activity compared with the wildtype-p85α/p110α
holoenzyme (Jaiswal et al., 2009). Holoenzymes
consisting of mutant p85α and p110α or p110α also
exhibited increased kinase activity (Jaiswal et al.,
2009). Philp et al. (2001) described a recurrent intronic
PIK3R1 mutation in ovarian cancer cells; the mutation
caused skipping of exon 13, resulting in deletion of
residues 551-670 within the iSH2/cSH2 domains of
p85α, and was associated with increased PI3K activity.
- Hyperphosphorylation of AKT: Mutants of p85α
that retained the ability to bind p110α also lead to
increased phosphorylation of AKT (Jaiswal et al.,
2009; Cheung et al., 2011; Urick et al., 2011).
- Dysregulation of PTEN stability: Cheung et al.,
(2011) showed that the p85α-E160X mutant, which
was present in an endometrial tumor and truncates
p85α within the BH domain, is associated with reduced
stability of the PTEN protein.
Somatic
Somatic mutations in PIK3R1 have been found in
endometrial cancers (26%, 34 of 133), cancers of the
central nervous system (4%, 26 of 657) and of the large
intestine (5%, 19 of 355), ovarian cancer (2%, 5 of
257), breast cancer (2%, 10 of 500), urothelial cancer
(0.7%, 1 of 145), squamous cell carcinoma of the skin
(11%, 1 of 9), pancreatic cancer (2%, 1 of 53), and in
hematological malignancy (1%, 3 of 472) (Philp et al.,
2001; Mizoughi et al., 2004; Shi et al., 2006; Sjoblom
et al., 2006; Jones et al., 2008; Parsons et al., 2008; The
Cancer Genome Research Atlas Network, 2008;
Bittinger et al., 2009; Jaiswal et al., 2009; Forbes et al.,
2010; Bettegowda et al., 2011; Kan et al., 2010; Park et
al., 2010b; Parsons et al., 2011; Cheung et al., 2011;
Sjodahl et al., 2011; The Cancer Genome Atlas
Research Network, 2011; Urick et al., 2011; Lipson et
al., 2012; Shah et al., 2012).
Mutation spectrum: Among 107 nonsynonymous,
somatic mutations of PIK3R1 catalogued in the
COSMIC database (v59 release, May 23rd, 2012)
(Forbes et al., 2010), 43% (46 of 107) of mutations are
in-frame insertions/deletions, 14% (15 of 107) are
nonsense mutations, 11.2% (12 of 107) are frameshift
mutations, 31.8% (34 of 107) are missense mutations.
The majority (68.2%, 73 of 107) of all somatic
mutations in PIK3R1 localize to animo acid residues
within the iSH2 domain, which is shared by all four
protein isoforms encoded by PIK3R1.
Altered functional properties of mutant proteins:
Biochemical and cellular studies of tumor-associated
p85α mutants have revealed functional differences
between mutant p85α and wild type p85α, as well as
functional differences among various p85α mutants
(Philp et al., 2001; Jaiswal et al., 2009; Sun et al., 2010;
Cheung et al., 2011; Urick et al., 2011).
- Transforming properties: Sun et al., (2010)
evaluated the ability of nine tumor-associated mutant
p85α proteins to transform chicken embryo fibroblasts.
The p85α-KS459delN and p85α-DKRMNS560del
mutants had the highest efficiency of transformation,
the p85α-R574fs and p85α-T576del mutants had
intermediate efficiency of transformation, and the
p85α-D560Y, p85α-N564K p85α-W583del, p85αE439del, and p85α-G376R mutants were only weakly
tansforming (Sun et al., 2010). Transformation was
mediated by p110α but not by p110α, p110α, or p110α
(Sun et al., 2010). Each of the nine p85α mutants
analyzed by Sun et al., retained the ability to bind
p110α and resulted in hyperphosphorylation of AKT
(T308) and 4E-BP1 when exogenously expressed in
CEF cells (Sun et al., 2010). Eight of the tumorassociated mutants analyzed by Sun et al., (2010)
localized to the iSH2 domain; one mutant (p85αG376R) localized to the nSH2 domain. Jaiswal et al.,
showed that the p85α-D560Y, p85α-N564D, and p85αQYL579delL mutants were capable of promoting both
the IL-3 independent growth and anchorage-
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
Implicated in
Endometrial cancer
Oncogenesis
Somatic mutations in PIK3R1 have been observed in
19%-43% of endometrioid endometrial carcinomas
(Cheung et al., 2011; Urick et al., 2011), in 8% of
serous endometrial carcinomas (Urick et al., 2011), in
20% of clear cell endometrial carcinomas (Urick et al.,
2011), and in 6% of endometrial carcinosarcomas
(Cheung et al., 2011).
Mutations in PIK3R1 tended to be mutually exclusive
with mutations in PIK3CA, which encodes the catalytic
subunit of PI3K, but co-occurred with mutations in
PTEN, and KRAS (Cheung et al., 2011; Urick et al.,
2011).
Glioblastoma
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
7% (20 of 276) of glioblastomas (Mizoughi et al.,
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PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha))
Bell DW
2004; Parsons et al., 2008; The Cancer Genome
Research Atlas Network, 2008; Park et al., 2010b). No
amplification or overexpression of PIK3R1 was
observed among 103 glioblastomas (Knobbe et al.,
2003).
Inukai K, Anai M, Van Breda E, Hosaka T, Katagiri H, Funaki
M, Fukushima Y, Ogihara T, Yazaki Y, Kikuchi, Oka Y, Asano
T. A novel 55-kDa regulatory subunit for phosphatidylinositol 3kinase structurally similar to p55PIK Is generated by alternative
splicing of the p85alpha gene. J Biol Chem. 1996 Mar
8;271(10):5317-20
Colorectal cancer
Liang J, Chen JK, Schreiber ST, Clardy J. Crystal structure of
P13K SH3 domain at 20 angstroms resolution. J Mol Biol. 1996
Apr 5;257(3):632-43
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
4% (10 of 228) of colorectal cancers (Philp et al., 2001;
Jaiswal et al., 2009; Park et al., 2010b), and in a
colorectal cancer cell line (Shi et al., 2006).
Musacchio A, Cantley LC, Harrison SC. Crystal structure of the
breakpoint
cluster
region-homology
domain
from
phosphoinositide 3-kinase p85 alpha subunit. Proc Natl Acad
Sci U S A. 1996 Dec 10;93(25):14373-8
Nolte RT, Eck MJ, Schlessinger J, Shoelson SE, Harrison SC.
Crystal structure of the PI 3-kinase p85 amino-terminal SH2
domain and its phosphopeptide complexes. Nat Struct Biol.
1996 Apr;3(4):364-74
Ovarian cancer
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
2% (5 of 257) of ovarian cancers (Philp et al., 2001;
Jaiswal et al., 2009; Kan et al., 2010; Park et al., 2010b;
The Cancer Genome Atlas Research Network, 2011).
Inukai K, Funaki M, Ogihara T, Katagiri H, Kanda A, Anai M,
Fukushima Y, Hosaka T, Suzuki M, Shin BC, Takata K, Yazaki
Y, Kikuchi M, Oka Y, Asano T. p85alpha gene generates three
isoforms of regulatory subunit for phosphatidylinositol 3-kinase
(PI 3-Kinase), p50alpha, p55alpha, and p85alpha, with
different PI 3-kinase activity elevating responses to insulin. J
Biol Chem. 1997 Mar 21;272(12):7873-82
Breast cancer
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
2% (10 of 500) of breast cancers (Sjoblom et al., 2006;
Jaiswal et al., 2009; Kan et al., 2010; Park et al., 2010b;
Jiao et al., 2012; Shah et al., 2012).
Baier LJ, Wiedrich C, Hanson RL, Bogardus C. Variant in the
regulatory subunit of phosphatidylinositol 3-kinase (p85alpha):
preliminary evidence indicates a potential role of this variant in
the acute insulin response and type 2 diabetes in Pima
women. Diabetes. 1998 Jun;47(6):973-5
Urothelial cancer
Hoedemaeker FJ, Siegal G, Roe SM, Driscoll PC, Abrahams
JP. Crystal structure of the C-terminal SH2 domain of the
p85alpha regulatory subunit of phosphoinositide 3-kinase: an
SH2 domain mimicking its own substrate. J Mol Biol. 1999 Oct
1;292(4):763-70
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
0.7% (1 of 145) of urothelial cancers (Sjodahl et al.,
2011).
Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP,
Whitehead
RH,
Thomas
RJ,
Phillips
WA.
The
phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in
human ovarian and colon tumors. Cancer Res. 2001 Oct
15;61(20):7426-9
Squamous cell carcinoma of the skin
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
8% (1 of 9) squamous cell carcinoma of the skin (Park
et al., 2010b).
Pancreatic cancer
Almind K, Delahaye L, Hansen T, Van Obberghen E, Pedersen
O, Kahn CR. Characterization of the Met326Ile variant of
phosphatidylinositol 3-kinase p85alpha. Proc Natl Acad Sci U
S A. 2002 Feb 19;99(4):2124-8
Oncogenesis
Somatic mutations in PIK3R1 have been reported in
16% (1 of 53) of pancreatic cancers (Jones et al., 2008;
Jaiswal et al., 2009; Kan et al., 2010).
Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF,
Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC,
Kahn CR. Reduced expression of the murine p85alpha subunit
of phosphoinositide 3-kinase improves insulin signaling and
ameliorates diabetes. J Clin Invest. 2002 Jan;109(1):141-9
Various human cancers
Knobbe CB, Reifenberger G. Genetic alterations and aberrant
expression of genes related to the phosphatidyl-inositol-3'kinase/protein kinase B (Akt) signal transduction pathway in
glioblastomas. Brain Pathol. 2003 Oct;13(4):507-18
Oncogenesis
By expression profiling, reduced expression of PIK3R1
has been noted in cancers of the prostate, lung, bladder,
ovary, breast, and liver (Taniguchi et al., 2010).
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