Prenylated C17orf37 Induces Filopodia Formation to Promote Cell Migration and Metastasis

Marilyne Kpetemey,Patrick J. Casey,Jamboor K. Vishwanatha,Ian Cushman,Subhamoy Dasgupta

doi:10.1074/jbc.m111.254599

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.

Highlights

Proposed to be a novel tumor biomarker [3]
Comparison of the 30 amino acids of C17orf37 preceding the CAAX motif with the known geranylgeranylated proteins RhoA, RhoB, RhoC, Rac1, and Cdc42 revealed the presence of multiple basic amino acids in C17orf37 protein as well (Fig. 1A)
In an attempt to understand the post-translational modifications of C17orf37 that may regulate its function, we identified a consensus prenylation motif CVIL at the C-terminal end

Summary

Introduction

Proposed to be a novel tumor biomarker [3]. In patients with metastatic breast cancer, aberrant expression of C17orf37 has been observed in distant metastatic sites such as lungs and liver, suggesting a possible role of C17orf37 protein in metastatic dissemination of cancer cells [3]. CAAX motif, we performed an in vitro prenylation assay using GST-fused C17orf37 (C17WT) and mutant form of C17orf37 in which Cys-112 was substituted with Ser (C17C112S) (supplemental Fig. S1A).

Results

Conclusion