DLC1 Interaction with S100A10 Mediates Inhibition of In Vitro Cell Invasion and Tumorigenicity of Lung Cancer Cells through a RhoGAP-Independent Mechanism
| Autor: | Nicholas C. Popescu, Xu-Yu Yang, Drazen B. Zimonjic |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Lung Neoplasms GTPase-activating protein Tumor suppressor gene Amino Acid Motifs Down-Regulation Breast Neoplasms Cell Growth Processes Article Cell surface receptor Carcinoma Non-Small-Cell Lung Cell Line Tumor Humans Medicine Annexin A2 Binding Sites biology business.industry Tumor Suppressor Proteins GTPase-Activating Proteins S100 Proteins HEK 293 cells Ubiquitination S100A10 Plasminogen Cell migration Cell biology HEK293 Cells Oncology Immunology biology.protein DLC1 business Protein Binding |
| Zdroj: | Cancer Research. 71:2916-2925 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-2158 |
| Popis: | The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein–protein interactions involving DLC1 in certain cancers. Cancer Res; 71(8); 2916–25. ©2011 AACR. |
| Databáze: | OpenAIRE |
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