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.

Low Molecular Weight Fraction of Commercial Human Serum Albumin Induces Morphologic and Transcriptional Changes of Bone Marrow-Derived Mesenchymal Stem Cells

“…Some research has even suggested that actin can be directly phosphorylated by AKT and that the cortical actin remodeling seen during filopodia formation is dependent on AKT-activated proteins [38]. Similarly, prenylated proteins identified for their involvement with filopodia formation in cancer cells have been implicated in migration and participate in the PI3K/AKT pathway [40]. Although we feel that the activity of LMWF5A is not limited to the activation of Akt, evidence suggests that some of the effects of this biologic on BMMSCs can be explained by stimulation of this pathway.…”

MIEN1 promotes oral cancer progression and implicates poor overall survival

“…[14][15][16][17]21 However, the role of MIEN1 in the tumor biology of OSCC has not been investigated. Here, we inquired whether MIEN1 is altered in OSCC, thus contributing to tumor progression and metastasis.…”

“…1C) suggesting possible posttranscriptional and/or post-translational regulation of MIEN1. 16,18 Confocal analysis (Fig. 1D) showed cytoplasmic localization of MIEN1.…”

“…15 MIEN1 also promotes migration by enabling actin cytoskeletal rearrangement through enhancement of finger-like actin filaments called filopodia. 16 Hence, though MIEN1 is not an oncogene directly, it aids cancer progression by playing key roles in distinct processes of migration and invasion of cancer cells.…”

Simvastatin downregulated C35 expression and inhibited the proliferation of colon cancer cells Lovo and HT29 <i>in vitro </i>

“…The 'CaaX' group of proteins are known to be farnesylated by the enzyme farnesyltransferase or geranylgeranylated by the enzyme geranylgeranyl transferase type I (GGTase-I) (14). This posttranslational modification of the C-terminal prenylation domain of C35 is essential for its membrane association, which facilitates the induction of filopodia formation (15). Because farnesyl and geranylgeranyl are generated from mevalonate (MVA) which is synthesized by HMG-CoA (16), inhibition of HMGCoA will reduce the production of MVA and in turn decrease the generation of farnesyl and geranylgeranyl, which finally influences the maturation and expression of C35.…”