DLC-1:a Rho GTPase-activating protein and tumour suppressor: Special Review Article

Abstract

Introduction The deleted in liver cancer family of RhoGAP domain proteins DLC-1 DLC-2 DLC-3 Invertebrate DLC-1-like proteins Expression of DLC family proteins Features of DLC family protein domains SAM domain RhoGAP domain START domain Serine-rich, unstructured middle region Biological functions of DLC-1 Cytoskeletal organization DLC-1 localizes to focal adhesions via binding to tensin family proteins Interaction of DLC-1 with caveolin-1 DLC-1 and phosphoinositide signalling Biological activities of DLC-2 and DLC-3 Genetic analysis of DLC-1 function Mouse DLC-1 gene knockout RhoGAP88 C in Drosophila The DLC family proteins in cancer Decreased expression of DLC-1 in human cancers Deletions of DLC1 in tumours Epigenetic inactivation of DLC-1 expression DLC-1 sequence variants in human cancers DLC-1 suppresses tumour cell growth DLC-1 as a metastasis suppressor gene Regulation of DLC-1 by anti-oncogenic factors Animal models of DLC-1 in cancer Evidence for roles of DLC-2 and DLC-3 in neoplasia Conclusions and future directions The deleted in liver cancer 1 (DLC-1) gene encodes a GTPase activating protein that acts as a negative regulator of the Rho family of small GTPases. Rho proteins transduce signals that influence cell morphology and physiology, and their aberrant up-regulation is a key factor in the neoplastic process, including metastasis. Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC-1 as a bona fide tumour suppressor gene in different types of human cancer. Loss of DLC-1 expression mediated by genetic and epigenetic mechanisms has been associated with the development of many human cancers, and restoration of DLC-1 expression inhibited the growth of tumour cells in vivo and in vitro. Two closely related genes, DLC-2 and DLC-3, may also be tumour suppressors. This review presents the current status of progress in understanding the biological functions of DLC-1 and its relatives and their roles in neoplasia. © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.