The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1.
The tensin family member cten (C-terminal tensin like) is an Src homology 2 (SH2) and phosphotyrosine binding domain-containing focal adhesion molecule that may function as a tumor suppressor. However, the mechanism has not been well established. We report that cten binds to another tumor suppressor, deleted in liver cancer 1 (DLC-1), and the SH2 domain of cten is responsible for the interaction. Unexpectedly, the interaction between DLC-1 and the cten SH2 domain is independent of tyrosine phosphorylation of DLC-1. By site-directed mutagenesis, we have identified several amino acid residues on cten and DLC-1 that are essential for this interaction. Mutations on DLC-1 perturb the interaction with cten and disrupt the focal adhesion localization of DLC-1. Furthermore, these DLC-1 mutants have lost their tumor suppression activities. When these DLC-1 mutants were fused to a focal adhesion targeting sequence, their tumor suppression activities were significantly restored. These results provide a novel mechanism whereby the SH2 domain of cten-mediated focal adhesion localization of DLC-1 plays an essential role in its tumor suppression activity.
Liao
Yi-Chun
YC
Center for Tissue Regeneration and Repair, University of California, Davis, Sacramento, CA 95817, USA.
Si
Lizhen
L
deVere White
Ralph W
RW
Lo
Su Hao
SH
D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D050505:Mutant Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport; D000070876:Tensins; D014162:Transfection; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D018909:src Homology Domains
D015815:Cell Adhesion Molecules; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D050505:Mutant Proteins; C000603371:TNS4 protein, human; D000070876:Tensins; C000603393:Tns4 protein, mouse; D025521:Tumor Suppressor Proteins; D019000:Phosphotyrosine