title: Prenylated c17orf37 induces filopodia formation to promote cell migration and metastasis.
abstract: Post-translational modification by covalent attachment of isoprenoid lipids (prenylation) regulates the functions and biological activities of several proteins implicated in the oncogenic transformation and metastatic progression of cancer. The largest group of prenylated proteins contains a CAAX motif at the C-terminal that serves as a substrate for a series of post-translational modifications that convert these otherwise hydrophilic proteins to lipidated proteins, thus facilitating membrane association. C17orf37 (chromosome 17 open reading frame 37), also known as C35/Rdx12/MGC14832, located in the 17q12 amplicon, is overexpressed in human cancer, and its expression correlates with the migratory and invasive phenotype of cancer cells. Here we show that C17orf37 contains a functional CAAX motif and is post-translationally modified by protein geranylgeranyltransferase-I (GGTase-I). Geranylgeranylation of C17orf37 at the CAAX motif facilitates association of the protein to the inner leaflet of plasma membrane, enhances migratory phenotype of cells by inducing increased filopodia formation, and potentiates directional migration. A prenylation-deficient mutant of C17orf37 is functionally inactive and fails to trigger dissemination of tail vein-injected cells in a mouse model of metastasis. These findings demonstrate that prenylation is required for the function of the C17orf37 protein in cancer cells and imply that the post-translational modification may functionally regulate metastatic progression of disease.
authors.affiliation: Department of Biomedical Sciences and Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
authors.forename: Subhamoy
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Ian
authors.initials: I
authors.lastname: Cushman
authors.forename: Marilyne
authors.initials: M
authors.lastname: Kpetemey
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
authors.forename: Jamboor K
authors.initials: JK
authors.lastname: Vishwanatha
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D017368:Protein Prenylation; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C517054:MIEN1 protein, human; D009363:Neoplasm Proteins; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I