title: PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion.
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.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue, New York, NY 10065, USA; Department of Biomedicine, University of Bergen, Jonas Liesvej 91, 5020 Bergen, Norway. Electronic address: nils.halberg@uib.no.
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Sengelaub
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Navrazhina
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue, New York, NY 10065, USA. Electronic address: stavazoie@rockefeller.edu.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; C107847:PITPNC1 protein, human; C529587:Rab1B protein, human; D020761:rab1 GTP-Binding Proteins