PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion

Cancer Cell. 2016 Mar 14;29(3):339-353. doi: 10.1016/j.ccell.2016.02.013.

Abstract

Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and overexpressed in metastatic breast, melanoma, and colon cancers. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism
  • Female
  • Golgi Apparatus / metabolism*
  • Humans
  • Melanoma / metabolism
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • rab1 GTP-Binding Proteins / metabolism*

Substances

  • Membrane Transport Proteins
  • PITPNC1 protein, human
  • Rab1B protein, human
  • rab1 GTP-Binding Proteins