Search results for PIK3R2

Showing 14 results out of 34

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Protein (2 results from a total of 2)

Identifier: R-HSA-74791
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PIK3R2: O00459
Identifier: R-HSA-3080554
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PIK3R2: O00459

Reaction (7 results from a total of 27)

Identifier: R-HSA-2394007
Species: Homo sapiens
Compartment: cytosol, plasma membrane
Constitutively active PI3K complex produces PIP3 in the absence of growth stimuli, resulting in aberrant activation of downstream AKT signaling that positively regulates cell growth and survival. The PIK3CA gene, encoding the catalytic subunit of PI3K (p110alpha), is one of the most frequently mutated oncogenes in cancer. Hotspot mutations are found in the helical domain and kinase domain of PIK3CA, with the most frequent mutations being E545K substitution in the helical domain and H1047R substitution in the kinase domain.
The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants.
In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly.
The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly.
Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated.
Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants.
Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011).
Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011).
For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009.
Identifier: R-HSA-109699
Species: Homo sapiens
Compartment: cytosol, plasma membrane, endosome membrane
PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2, facilitating phosphorylation (Mandelker et al. 2009, Burke et al. 2011; reviewed in Koyasu et al, 2003; Engelman et al, 2006).
Identifier: R-HSA-5654643
Species: Homo sapiens
Compartment: cytosol, extracellular region, plasma membrane
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
Identifier: R-HSA-5654622
Species: Homo sapiens
Compartment: cytosol, extracellular region, plasma membrane
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
Identifier: R-HSA-5654662
Species: Homo sapiens
Compartment: cytosol, extracellular region, plasma membrane
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
Identifier: R-HSA-5654614
Species: Homo sapiens
Compartment: cytosol, extracellular region, plasma membrane
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
Identifier: R-HSA-5654669
Species: Homo sapiens
Compartment: cytosol, extracellular region, plasma membrane
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).

Set (4 results from a total of 4)

Identifier: R-HSA-391342
Species: Homo sapiens
Compartment: cytosol
There are five variants of the PI3K regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta and p55gamma (there are also three variants of the p110 catalytic subunit designated p110alpha, beta, or delta). The first three regulatory subunits are all splice variants of PIK3R1 (p85 or regulatory subunit alpha), the other two are expressed by PIK3R2 and PIK3R3, known as p85 beta, and p55 gamma, respectively. The most highly expressed regulatory subunit is p85alpha. The 3 variants forms of p85 alpha are not explicitly represented in this set.
Identifier: R-HSA-1295511
Species: Homo sapiens
Compartment: cytosol
There are five variants of the PI3K regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta and p55gamma (there are also three variants of the p110 catalytic subunit designated p110alpha, beta, or delta). The first three regulatory subunits are all splice variants of PIK3R1 (p85 or regulatory subunit alpha), the other two are expressed by PIK3R2 and PIK3R3, known as p85 beta, and p55 gamma, respectively. The most highly expressed regulatory subunit is p85alpha. The 3 variants forms of p85 alpha are not explicitly represented in this set.
Identifier: R-HSA-508248
Species: Homo sapiens
Compartment: cytosol
This set represents Class 1A PI3Ks including all three genes that can give rise to the five isoforms of the regulatory subunit. Note that the p85 alpha form is almost always the form used as a reagent experimentally and measured by p85-Abs.The other forms are rarely used or determined experimentally. Also note that Class 1A PI3Ks may not be the most relevant physiologically in some cell types (e.g. T cells). There are five variants of the p85 regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta, and p55gamma. There are also three variants of the p110 catalytic subunit designated p110alpha, beta, or gamma catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two are expressed by Pik3r2 and Pik3r3, respectively). The most highly expressed regulatory subunit is p85alpha. All three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110alpha, p110beta and p110gamma, respectively). The alpha and beta p110s are expressed in all cells, while p110gamma is expressed primarily in leukocytes. It has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic p110gamma subunits comprise the class IB PI3Ks, each is encoded by a single gene.
Identifier: R-HSA-3080553
Species: Homo sapiens
Compartment: cytosol
This set represents Class 1A PI3Ks including all three genes that can give rise to the five isoforms of the regulatory subunit. Note that the p85 alpha form is almost always the form used as a reagent experimentally and measured by p85-Abs.The other forms are rarely used or determined experimentally. Also note that Class 1A PI3Ks may not be the most relevant physiologically in some cell types (e.g. T cells). There are five variants of the p85 regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta, and p55gamma. There are also three variants of the p110 catalytic subunit designated p110alpha, beta, or gamma catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two are expressed by Pik3r2 and Pik3r3, respectively). The most highly expressed regulatory subunit is p85alpha. All three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110alpha, p110beta and p110gamma, respectively). The alpha and beta p110s are expressed in all cells, while p110gamma is expressed primarily in leukocytes. It has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic p110gamma subunits comprise the class IB PI3Ks, each is encoded by a single gene.

Pathway (1 results from a total of 1)

Identifier: R-HSA-2219528
Species: Homo sapiens
Class IA PI3K is a heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). In the absence of activating signals, the regulatory subunit stabilizes the catalytic subunit while inhibiting its activity. The complex becomes activated when extracellular signals stimulate the phosphorylation of the cytoplasmic domains of transmembrane receptors or receptor-associated proteins. The p85 regulatory subunit binds phosphorylated motifs of activator proteins, which induces a conformational change that relieves p85-mediated inhibition of the p110 catalytic subunit and enables PI3K to phosphorylate PIP2 to form PIP3. The phosphoinositide kinase activity of PI3K is opposed by the phosphoinositide phosphatase activity of PTEN.

PIP3 acts as a messenger that recruits PDPK1 (PDK1) and AKT (AKT1, AKT2 or AKT3) to the plasma membrane. PDPK1 also possesses a low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane. Binding of AKT to PIP3 induces a conformational change that enables TORC2 complex to phosphorylate AKT at a conserved serine residue (S473 in AKT1). Phosphorylation at the serine residue enables AKT to bind to PDPK1 and exposes a conserved threonine residue (T308) that is phosphorylated by PDPK1. AKT phosphorylated at both serine and threonine residues dissociates from the plasma membrane and acts as a serine/threonine kinase that phosphorylates a number of cytosolic and nuclear targets involved in regulation of cell metabolism, survival and gene expression. For a recent review, please refer to Manning and Cantley, 2007.
Signaling by PI3K/AKT is frequently constitutively activated in cancer. This activation can be via gain-of-function mutations in PI3KCA (encoding catalytic subunit p110alpha), PIK3R1 (encoding regulatory subunit p85alpha) and AKT1. The PI3K/AKT pathway can also be constitutively activated by loss-of-function mutations in tumor suppressor genes such as PTEN.
Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011). While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008).
Loss-of-function mutations affecting the phosphatase domain of PTEN are frequently found in sporadic cancers (Kong et al. 1997, Lee et al. 1999, Han et al. 2000), as well as in PTEN hamartoma tumor syndromes (PHTS) (Marsh et al. 1998). PTEN can also be inactivated by gene deletion or epigenetic silencing, or indirectly by overexpression of microRNAs that target PTEN mRNA (Huse et al. 2009). Cells with deficient PTEN function have increased levels of PIP3, and therefore increased AKT activity. For a recent review, please refer to Hollander et al. 2011.
Because of their clear involvement in human cancers, PI3K and AKT are targets of considerable interest in the development of small molecule inhibitors. Although none of the currently available inhibitors display preference for mutant variants of PIK3CA or AKT, several inhibitors targeting the wild-type kinases are undergoing clinical trials. These include dual PI3K/mTOR inhibitors, class I PI3K inhibitors, pan-PI3K inhibitors, and pan-AKT inhibitors. While none have yet been approved for clinical use, these agents show promise for future therapeutics. In addition, isoform-specific PI3K and AKT inhibitors are currently being developed, and may provide more specific treatments along with reduced side-effects. For a recent review, please refer to Liu et al. 2009.
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