Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation

Bijay S. Jaiswal; Vasantharajan Janakiraman; Noelyn M. Kljavin; Subhra Chaudhuri; Howard M. Stern; Weiru Wang; Zhengyan Kan; Hashem A. Dbouk; Brock A. Peters; Paul Waring; Trisha Dela Vega; Denise M. Kenski; Krista K. Bowman; Maria Lorenzo; Hong Li; Jiansheng Wu; Zora Modrusan; Jeremy Stinson; Michael Eby; Peng Yue; Josh S. Kaminker; Frederic J. de Sauvage; Jonathan M. Backer; Somasekar Seshagiri

doi:10.1016/j.ccr.2009.10.016

Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation

Bijay S. Jaiswal, Vasantharajan Janakiraman, Noelyn M. Kljavin, Subhra Chaudhuri, Howard M. Stern, Weiru Wang, Zhengyan Kan, Hashem A. Dbouk, Brock A. Peters, Paul Waring, Trisha Dela Vega, Denise M. Kenski, Krista K. Bowman, Maria Lorenzo, Hong Li, Jiansheng Wu, Zora Modrusan, Jeremy Stinson, Michael Eby, Peng YueJosh S. Kaminker, Frederic J. de Sauvage, Jonathan M. Backer, Somasekar Seshagiri

Molecular Pharmacology

Research output: Contribution to journal › Article › peer-review

250 Scopus citations

Abstract

Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation, and motility. Oncogenic activating mutations in the p110α catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85α in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85α's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85α mutants promote cell survival, AKT activation, anchorage-independent cell growth, and oncogenesis in a p110-dependent manner.

Original language	English (US)
Pages (from-to)	463-474
Number of pages	12
Journal	Cancer Cell
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2009.10.016
State	Published - Dec 8 2009

Keywords

CELLCYCLE
SIGNALING

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2009.10.016

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Jaiswal, B. S., Janakiraman, V., Kljavin, N. M., Chaudhuri, S., Stern, H. M., Wang, W., Kan, Z., Dbouk, H. A., Peters, B. A., Waring, P., Dela Vega, T., Kenski, D. M., Bowman, K. K., Lorenzo, M., Li, H., Wu, J., Modrusan, Z., Stinson, J., Eby, M., ... Seshagiri, S. (2009). Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation. Cancer Cell, 16(6), 463-474. https://doi.org/10.1016/j.ccr.2009.10.016

Jaiswal, BS, Janakiraman, V, Kljavin, NM, Chaudhuri, S, Stern, HM, Wang, W, Kan, Z, Dbouk, HA, Peters, BA, Waring, P, Dela Vega, T, Kenski, DM, Bowman, KK, Lorenzo, M, Li, H, Wu, J, Modrusan, Z, Stinson, J, Eby, M, Yue, P, Kaminker, JS, de Sauvage, FJ, Backer, JM & Seshagiri, S 2009, 'Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation', Cancer Cell, vol. 16, no. 6, pp. 463-474. https://doi.org/10.1016/j.ccr.2009.10.016

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title = "Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation",

abstract = "Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation, and motility. Oncogenic activating mutations in the p110α catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85α in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85α's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85α mutants promote cell survival, AKT activation, anchorage-independent cell growth, and oncogenesis in a p110-dependent manner.",

keywords = "CELLCYCLE, SIGNALING",

author = "Jaiswal, {Bijay S.} and Vasantharajan Janakiraman and Kljavin, {Noelyn M.} and Subhra Chaudhuri and Stern, {Howard M.} and Weiru Wang and Zhengyan Kan and Dbouk, {Hashem A.} and Peters, {Brock A.} and Paul Waring and {Dela Vega}, Trisha and Kenski, {Denise M.} and Bowman, {Krista K.} and Maria Lorenzo and Hong Li and Jiansheng Wu and Zora Modrusan and Jeremy Stinson and Michael Eby and Peng Yue and Kaminker, {Josh S.} and {de Sauvage}, {Frederic J.} and Backer, {Jonathan M.} and Somasekar Seshagiri",

note = "Funding Information: The authors would like to acknowledge Genentech DNA Sequencing, Oligo, Microarray, and FACS laboratories for their help with the project. We thank the Genentech Bioinformatics group for informatics infrastructure support and the Pathology Core Laboratories for providing histology, immunohistochemistry, and tissue management support. Thanks to C. Dant, R. Kelly, K. Newton, and J. Theunissen for their critical reading of the manuscript. Work in J.M.B.'s laboratory was supported by a grant from the Janey Fund and National Institutes of Health grant GM55692. Special thanks to L.C. Cantley for the pan-p85 null MEFs. The majority of the authors are employees of Genentech Inc., as indicated. ",

year = "2009",

month = dec,

day = "8",

doi = "10.1016/j.ccr.2009.10.016",

language = "English (US)",

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pages = "463--474",

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T1 - Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation

AU - Jaiswal, Bijay S.

AU - Janakiraman, Vasantharajan

AU - Kljavin, Noelyn M.

AU - Chaudhuri, Subhra

AU - Stern, Howard M.

AU - Wang, Weiru

AU - Kan, Zhengyan

AU - Dbouk, Hashem A.

AU - Peters, Brock A.

AU - Waring, Paul

AU - Dela Vega, Trisha

AU - Kenski, Denise M.

AU - Bowman, Krista K.

AU - Lorenzo, Maria

AU - Li, Hong

AU - Wu, Jiansheng

AU - Modrusan, Zora

AU - Stinson, Jeremy

AU - Eby, Michael

AU - Yue, Peng

AU - Kaminker, Josh S.

AU - de Sauvage, Frederic J.

AU - Backer, Jonathan M.

AU - Seshagiri, Somasekar

N1 - Funding Information: The authors would like to acknowledge Genentech DNA Sequencing, Oligo, Microarray, and FACS laboratories for their help with the project. We thank the Genentech Bioinformatics group for informatics infrastructure support and the Pathology Core Laboratories for providing histology, immunohistochemistry, and tissue management support. Thanks to C. Dant, R. Kelly, K. Newton, and J. Theunissen for their critical reading of the manuscript. Work in J.M.B.'s laboratory was supported by a grant from the Janey Fund and National Institutes of Health grant GM55692. Special thanks to L.C. Cantley for the pan-p85 null MEFs. The majority of the authors are employees of Genentech Inc., as indicated.

PY - 2009/12/8

Y1 - 2009/12/8

N2 - Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation, and motility. Oncogenic activating mutations in the p110α catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85α in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85α's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85α mutants promote cell survival, AKT activation, anchorage-independent cell growth, and oncogenesis in a p110-dependent manner.

AB - Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation, and motility. Oncogenic activating mutations in the p110α catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85α in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85α's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85α mutants promote cell survival, AKT activation, anchorage-independent cell growth, and oncogenesis in a p110-dependent manner.

KW - CELLCYCLE

KW - SIGNALING

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U2 - 10.1016/j.ccr.2009.10.016

DO - 10.1016/j.ccr.2009.10.016

M3 - Article

C2 - 19962665

AN - SCOPUS:70749140937

SN - 1535-6108

VL - 16

SP - 463

EP - 474

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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