Untitled

Abstract

Rho GTPases are key transducers of several fundamental cellular processes such as cell division, adhesion, migration, polarity, cytoskeletal remodeling, and apoptosis [3]. They act as molecular switches that cycle between an inactive GDP-bound and an active GTP-bound form in response to intra-or extracellular signaling. This GDP/GTP cycle is carefully controlled by three classes of regulatory proteins: the Rho-GEFs (guanine nucleotide exchange factors) that catalyze the exchange of GDP for GTP, the Rho-GAPs (GTPase activating proteins) that hydrolyze GTP to GDP, and the Rho-GDIs (guanine nucleotide dissociation inhibitors) that form a complex with the GDP-bound form of Rho proteins and prevent nucleotide exchange as well as sequester the Rho GTPases in the cytoplasm. During cell spreading and migration, Rho GTPases control the formation of focal complexes, their maturation to focal adhesions, and the continuous turnover of these structures, along with many aspects of actin cytoskeletal dynamics, including stress fiber formation. Dysregulation of Rho GTPases is associated with diverse abnormal phenotypes and several diseases, including cancer. One Rho regulator that has frequently been implicated in cancer is the tumor suppressor Deleted in Liver Cancer 1 (DLC1; also known as STARD12 or ARHGAP7). DLC1 encodes a Rho-GAP that negatively regulates Rho by converting active GTP-bound Rho to inactive GDP-bound Rho, is associated with focal adhesions, and is down-regulated in many tumor types.The most abundant translation product of the human DLC1 gene, which is located at chromosome 8p21-22, is a 1091 amino acid protein that contains three well recognized domains: an N-terminal sterile alpha motif (SAM) domain, a C-terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain, and the Rho-GAP domain, located upstream from the START domain [1,2,5]. A Serine-rich Linker region (LR) lies between the SAM and the Rho-GAP domains. A segment within the LR is sometimes referred to as the Focal Adhesion Targeting (FAT) domain because DLC1 is recruited to focal adhesions via this region. The multidomain structure of DLC1 suggests that it might interact with several other functionally important proteins, and several DLC1 binding partners, in addition to Rho-GTP, have been identified and found to contribute to the biology of DLC1 [1,5]. Two other structurally related proteins of the DLC family, DLC2 (STARD13), and DLC3 (KIAA0189 or STARD8) have also been identified.Although all three members of the family are widely expressed in normal tissues, only DLC1 knockout mice are embryonic lethal, while DLC2 and DLC3 knockout mice are viable, which suggests DLC1 is essential for embryonic development. In cancer, downregulation of DLC1 is also more important than DLC2 and DLC3 [7]. Fibroblasts cultured from DLC1-deficient mouse embryos have shown significant alterations in the cytoskeleton organization of actin filaments and focal adhesions, suggesting a crucial role for DLC1 in these processes in normal cells [2].D...

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