Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities.

Abstract

The three deleted in liver cancer genes (DLC1-3) encode Rho-GTPase-activating proteins (RhoGAPs) whose expression is frequently down-regulated or silenced in a variety of human malignancies. The RhoGAP activity is required for full DLC-dependent tumor suppressor activity. Here we report that DLC1 and DLC3 bind to human tensin1 and its chicken homolog. The binding has been mapped to the tensin Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains at the C terminus of tensin proteins. Distinct DLC1 sequences are required for SH2 and PTB binding. DCL binding to both domains is constitutive under basal conditions. The SH2 binding depends on a tyrosine in DCL1 (Y442) but is phosphotyrosine-independent, a highly unusual feature for SH2 binding. DLC1 competed with the binding of other proteins to the tensin C terminus, including beta 3-integrin binding to the PTB domain. Point mutation of a critical tyrosine residue (Y442F) in DLC1 rendered the protein deficient for binding the tensin SH2 domain and binding full-length tensin. The Y442F protein was diffusely cytoplasmic, in contrast to the localization of wild-type DLC1 to focal adhesions, but it retained the ability to reduce the intracellular levels of Rho-GTP. The Y442F mutant displayed markedly reduced biological activity, as did a mutant that was RhoGAP-deficient. The results suggest that DLC1 is a multifunctional protein whose biological activity depends on cooperation between its tensin binding and RhoGAP activities, although neither activity depends on the other.

• Authors: Xiaolan Qian, Guorong Li, Holly K Asmussen, Laura Asnaghi, William C Vass, Richard Braverman, Kenneth M Yamada, Nicholas C Popescu, Alex G Papageorge, Douglas R Lowy
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 21 Pg. 9012-7 (May 22 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17517630 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• GTPase-Activating Proteins
• Integrins
• Microfilament Proteins
• Oncogene Proteins
• STARD8 protein, human
• TNS1 protein, human
• Tensins
• Tns1 protein, mouse
• Tumor Suppressor Proteins
• rho GTPase-activating protein
• Phosphotyrosine
• Tyrosine

Topics

• Animals
• Cell Line
• GTPase-Activating Proteins (metabolism)
• Humans
• Integrins (metabolism)
• Mice
• Microfilament Proteins (metabolism)
• Mutation (genetics)
• Oncogene Proteins (genetics, metabolism)
• Phosphotyrosine (metabolism)
• Protein Binding
• Tensins
• Tumor Suppressor Proteins (genetics, metabolism)
• Tyrosine (genetics, metabolism)
• src Homology Domains