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PMID: 16432180 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 5 ·2006-01-31 ·Pages 1289-94

Kang S, Denley A, Vanhaesebroeck B, Vogt PK

Abstract

Class I phosphoinositide 3-kinase contains four isoforms of the catalytic subunit, p110alpha, -beta, -gamma, and -delta. At physiological levels of expression, the wild-type p110alpha isoform lacks oncogenic potential, but gain-of-function mutations and overexpression of p110alpha are correlated with oncogenicity. The p110beta, -gamma, and -delta isoforms induce transformation of cultured cells as wild-type proteins. This oncogenic potential requires kinase activity and can be suppressed by the target of rapamycin inhibitor rapamycin. The p110delta isoform constitutively activates the Akt signaling pathway; p110gamma activates Akt only in the presence of serum. The isoforms differ in their requirements for upstream signaling. The transforming activity of the p110gamma isoform depends on rat sarcoma viral oncogene homolog (Ras) binding; preliminary data suggest the same for p110beta and indicate Ras-independent oncogenic potential of p110delta. The surprising oncogenic potential of the wild-type non-alpha isoforms of class I phosphoinositide 3-kinase may explain the dearth of cancer-specific mutations in these proteins, because these non-alpha isoforms could contribute to the oncogenic phenotype of the cell by differential expression.

MeSH Terms
Animals Antibiotics, Antineoplastic/pharmacology Blotting, Western Cell Differentiation Cell Line, Tumor Cell Transformation, Neoplastic Cells, Cultured Chick Embryo Class I Phosphatidylinositol 3-Kinases Culture Media, Serum-Free/pharmacology Humans Mutagenesis, Site-Directed Mutation Phosphatidylinositol 3-Kinases/chemistry,metabolism Plasmids/metabolism Point Mutation Protein Binding Protein Isoforms Protein Kinases/metabolism Signal Transduction Sirolimus/pharmacology TOR Serine-Threonine Kinases Time Factors Transfection ras Proteins/metabolism
Chemicals
Antibiotics, Antineoplastic Culture Media, Serum-Free Protein Isoforms Protein Kinases MTOR protein, human mTOR protein, rat Class I Phosphatidylinositol 3-Kinases PIK3CB protein, human TOR Serine-Threonine Kinases ras Proteins Sirolimus
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kang Sohye
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC 239, La Jolla, CA 92037, USA.
Denley Adam
Vanhaesebroeck Bart
Vogt Peter K
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0510772103
Published
2006-01-31
Epub
2006-00-23
Pages
1289-94
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1360601
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0510772103 PMC Full Text View journal details
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