Article

Nature 459, 1085-1090 (25 June 2009) | doi:10.1038/nature08109; Received 19 October 2008; Accepted 7 May 2009

GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer

Kenneth L. Scott1,9, Omar Kabbarah1,9, Mei-Chih Liang1,4, Elena Ivanova2, Valsamo Anagnostou5, Joyce Wu1, Sabin Dhakal1, Min Wu1, Shujuan Chen1, Tamar Feinberg1, Joseph Huang1, Abdel Saci6, Hans R. Widlund3,7, David E. Fisher3,8, Yonghong Xiao2, David L. Rimm5, Alexei Protopopov2, Kwok-Kin Wong1,4 & Lynda Chin1,2,7

  1. Department of Medical Oncology,
  2. Belfer Institute for Applied Cancer Science,
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute,
  4. Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA
  5. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
  6. Department of Systems Biology, Harvard Medical School,
  7. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  8. Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
  9. These authors contributed equally to this work.

Correspondence to: Lynda Chin1,2,7 Correspondence and requests for materials should be addresses to L.C. (Email: lynda_chin@dfci.harvard.edu).

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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 trans-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 FRAP1) 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.

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