G0LPH3 modulates mTOR signalling and rapamydn sensitivity in cancer

Kenneth L. Scott, Omar Kabbarah, Mei Chih Liang, Elena Ivanova, Valsamo Anagnostou, Joyce Wu, Sabin Dhakal, Min Wu, Shujuan Chen, Tamar Feinberg, Joseph Huang, Abdel Saci, Hans R. Widlund, David E. Fisher, Yonghong Xiao, David L. Rimm, Alexei Protopopov, Kwok Kin Wong, Lynda Chin

Research output: Contribution to journalArticle

Abstract

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the rrans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAPI) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.

Original languageEnglish (US)
Pages (from-to)1085-1090
Number of pages6
JournalNature
Volume459
Issue number7250
DOIs
StatePublished - Jun 25 2009
Externally publishedYes

ASJC Scopus subject areas

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    Scott, K. L., Kabbarah, O., Liang, M. C., Ivanova, E., Anagnostou, V., Wu, J., Dhakal, S., Wu, M., Chen, S., Feinberg, T., Huang, J., Saci, A., Widlund, H. R., Fisher, D. E., Xiao, Y., Rimm, D. L., Protopopov, A., Wong, K. K., & Chin, L. (2009). G0LPH3 modulates mTOR signalling and rapamydn sensitivity in cancer. Nature, 459(7250), 1085-1090. https://doi.org/10.1038/nature08109