The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations

Huang, Chuan Hsiang; Mandelker, Diana; Schmidt‐Kittler, Oleg; Samuels, Yardena; Velculescu, Victor E.; Kinzler, Kenneth W.; Vogelstein, Bert; Gabelli, Sandra B.; Amzel, L. Mario

doi:10.1126/science.1150799

Cited by 511 publications

(534 citation statements)

References 57 publications

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“…In contrast, mutations in the helical domain (exon 9) cluster on an exposed surface patch of the protein and may change its ability to interact with other regulatory proteins, which may be different for each tissue. [31][32][33] As expected, analyses of the PTEN mutations revealed that these alterations are more common in pure endometrioid adenocarcinomas compared with that in non-endometrioid adenocarcinomas and mixed tumors. Different studies of colorectal and breast carcinomas have claimed that the PIK3CA and PTEN mutations are mutually exclusive and suggest that carcinogenic signaling through this pathway occurs either through the activation of PIK3CA or inactivation of PTEN.…”

Section: Discussionsupporting

confidence: 76%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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The status of p53 and the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) signaling pathway was investigated in 132 endometrial carcinomas, including endometrioid endometrial carcinomas, non-endometrioid endometrial carcinomas, and mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these tumors. Molecular genetic differences between low-grade and high-grade endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade endometrioid adenocarcinomas. In contrast, non-endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of carcinoma. Carcinomas with exon 20 PIK3CA mutations or PIK3CA mRNA overexpression were often high-grade carcinomas associated with myometrial invasion; in contrast, tumors that carried exon 9 mutations were more likely to be low-grade carcinomas. The Kaplan-Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P ¼ 0.000). Although alterations in the PI3K-AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K-AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P ¼ 0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial carcinogenesis.

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Section: Discussionsupporting

confidence: 76%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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“…3, A and B). The essential role of p110␣ in the heparanase-AKT pathway provides further molecular evidence for the tumorigenic properties of heparanase, because activating mutations in this isoform are oncogenic and have been found in many tumors (43,44). (iii) The activation of PI3K/AKT by heparanase was inefficient if the PI3K-RAS interaction was prevented (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

Riaz

Ilan²,

Vlodavsky³

et al. 2013

Journal of Biological Chemistry

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Background: Heparanase levels are associated with tumor metastasis. Latent heparanase induces the prosurvival PI3K-AKT pathway via uncharacterized mechanisms. Results: AKT activation by heparanase involved PI3K p110␣, RAS, RICTOR, a PP2-sensitive kinase, FAK or PYK2, and ␤1 or ␤3 integrin-mediated adhesion. Conclusion:The heparanase receptor(s) intimately cooperates with integrins during induction of the PI3K-AKT pathway. Significance: Key steps in the heparanase-PI3K-AKT axis were identified.

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“…First of all, analysis of the relative positions of the nSH2 and iSH2 domains within p85ni by pulsed EPR spectroscopy in frozen solution suggest the presence of significant disorder between the nSH2 and iSH2 domains (K. I. Sen and G. J. Gerfen, unpublished observations). Furthermore, the identification of contacts between the C2 domain of p110␣ and residues around 560-564 in the iSH2 domain led to an alternative model, in which truncation at 572 would destabilize C2-iSH2 domain contacts that are required for inhibition of p110␣ (16,32).…”

mentioning

confidence: 99%

“…While NMR, EPR, and crystal structures have been obtained for the individual domains (7)(8)(9)(10)(11)(12)(13)(14)(15), there are currently no structures that define how these domains are arranged in space. The p110␣ catalytic subunit has been better defined, with structures of the N-terminal adapter-binding domain (ABD) or the entire p110␣ bound to the coiled coil (iSH2) domain of p85 (15,16). Like the related Class IB catalytic subunit p110␥ (17), p110␣ contains Ras-binding, C2, helical, and kinase domains.…”

mentioning

confidence: 99%

Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants

Shekar

Flinn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We previously proposed a model of Class IA PI3K regulation in which p85 inhibition of p110␣ requires (i) an inhibitory contact between the p85 nSH2 domain and the p110␣ helical domain, and (ii) a contact between the p85 nSH2 and iSH2 domains that orients the nSH2 so as to inhibit p110␣. We proposed that oncogenic truncations of p85 fail to inhibit p110 due to a loss of the iSH2-nSH2 contact. However, we now find that within the context of a minimal regulatory fragment of p85 (the nSH2-iSH2 fragment, termed p85ni), the nSH2 domain rotates much more freely ( c Ϸ12.7 ns) than it could if it were interacting rigidly with the iSH2 domain. These data are not compatible with our previous model. We therefore tested an alternative model in which oncogenic p85 truncations destabilize an interface between the p110␣ C2 domain (residue N345) and the p85 iSH2 domain (residues D560 and N564). p85ni-D560K/N564K shows reduced inhibition of p110␣, similar to the truncated p85ni-572 STOP . Conversely, wild-type p85ni poorly inhibits p110␣N345K. Strikingly, the p110␣N345K mutant is inhibited to the same extent by the wild-type or truncated p85ni, suggesting that mutation of p110␣-N345 is not additive with the p85ni-572 STOP mutation. Similarly, the D560K/N564K mutation is not additive with the p85ni-572 STOP mutant for downstream signaling or cellular transformation. Thus, our data suggests that mutations at the C2-iSH2 domain contact and truncations of the iSH2 domain, which are found in human tumors, both act by disrupting the C2-iSH2 domain interface.cancer ͉ glioblastoma ͉ phosphoinositide 3-kinase ͉ PIK3CA P I 3-kinases are important cellular regulators of growth, survival, and motility, and deregulation of PI 3-kinase signaling contributes to cancer and other human diseases (1). Class IA PI 3-kinases, which produce PI[3,4,5]P3 in intact cells (2), are obligate heterodimers of a regulatory subunit (p85␣, p85␤, p55␣, p50␣, or p55␥) and a catalytic subunit (p110␣, p110␤, or p110␦) (reviewed in ref.3). The regulatory subunits have two major functions: they stabilize the catalytic subunits against thermal denaturation, and they maintain the catalytic subunit in an inhibited, low activity state (4, 5).p85 and p110 are both multidomain proteins that bind to each other and to upstream activators such as Rac and Cdc42, Ras, and tyrosine phosphorylated receptors and adapters (reviewed in ref. 6). p85 contains an SH3 domain, a Rac/Cdc42-binding domain homologous to a GAP domain in the BCR gene product, and two SH2 domains that flank an antiparallel coiled coil domain (the iSH2 domain). While NMR, EPR, and crystal structures have been obtained for the individual domains (7-15), there are currently no structures that define how these domains are arranged in space. The p110␣ catalytic subunit has been better defined, with structures of the N-terminal adapter-binding domain (ABD) or the entire p110␣ bound to the coiled coil (iSH2) domain of p85 (15,16). Like the related Class IB catalytic subunit p110␥ (17), p110␣ contains Ras-binding, C2, ...

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The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations

Cited by 511 publications

References 57 publications

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants

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