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

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

Research output: Contribution to journalArticle

Abstract

The three deleted in liver cancer genes (DLC1-3) encode RhoGTPase-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 β3-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.

Original languageEnglish (US)
Pages (from-to)9012-9017
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number21
DOIs
StatePublished - May 22 2007
Externally publishedYes

Fingerprint

Neoplasm Genes
Liver Neoplasms
Phosphotyrosine
Proteins
Tyrosine
Focal Adhesions
src Homology Domains
Guanosine Triphosphate
rho GTPase-activating protein
Tensins
Point Mutation
Protein Binding
Integrins
Chickens
Neoplasms
Carrier Proteins

Keywords

  • DLC1
  • Src homology 2 and phosphotyrosine binding domains
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. / Qian, Xiaolan; Li, Guorong; Asmussen, Holly K.; Asnaghi, Laura; Vass, William C.; Braverman, Richard; Yamada, Kenneth M.; Popescu, Nicholas C.; Papageorge, Alex G.; Lowy, Douglas R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 21, 22.05.2007, p. 9012-9017.

Research output: Contribution to journalArticle

Qian, Xiaolan ; Li, Guorong ; Asmussen, Holly K. ; Asnaghi, Laura ; Vass, William C. ; Braverman, Richard ; Yamada, Kenneth M. ; Popescu, Nicholas C. ; Papageorge, Alex G. ; Lowy, Douglas R. / Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 21. pp. 9012-9017.
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T1 - Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities

AU - Qian, Xiaolan

AU - Li, Guorong

AU - Asmussen, Holly K.

AU - Asnaghi, Laura

AU - Vass, William C.

AU - Braverman, Richard

AU - Yamada, Kenneth M.

AU - Popescu, Nicholas C.

AU - Papageorge, Alex G.

AU - Lowy, Douglas R.

PY - 2007/5/22

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N2 - The three deleted in liver cancer genes (DLC1-3) encode RhoGTPase-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 β3-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.

AB - The three deleted in liver cancer genes (DLC1-3) encode RhoGTPase-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 β3-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.

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