title: Tensin1 positively regulates RhoA activity through its interaction with DLC1.
abstract: DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA. Electronic address: ypshih@ucdavis.edu.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Shih
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA.
authors.forename: Aifeng
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA.
authors.forename: Su Hao
authors.initials: SH
authors.lastname: Lo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000737:chemistry / Q000502:physiology*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D000070876:Tensins; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C430864:DLC-1 (deleted in liver cancer) protein, mouse; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; C000603369:TNS1 protein, human; D000070876:Tensins; C000603373:Tns1 protein, mouse; D025521:Tumor Suppressor Proteins; D020742:rhoA GTP-Binding Protein
keywords: Angiogenesis; DLC1; Focal adhesion; RhoA; Tensin