Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor Journal Article
| Authors: | Georgescu, M. M.; Kirsch, K. H.; Kaloudis, P.; Yang, H.; Pavletich, N. P.; Hanafusa, H. |
| Article Title: | Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor |
| Abstract: | PTEN is a tumor suppressor frequently inactivated in brain, prostate, and uterine cancer. It acts as a phosphoinositide phosphatase and consists of an amino-terminal phosphatase domain tightly linked to a COOH-terminal C2 domain involved in lipid membrane-binding, We investigated the functions of the C2 domain and their relevance for tumor growth. To discriminate between PTEN C2 domain ability to recruit or to position the active site to the membrane, we artificially membrane-targeted PTEN by a myristoylation signal. This modification increased wild-type PTEN growth inhibition but did not rescue a C2 mutant defective in lipid-binding, suggesting a model in which PTEN C2 domain positions the active site productively with respect to the membrane-bound phosphoinositide substrate. When tumor-derived mutations in the loops that connect the C2 beta -strands were analyzed, we found that these generally destabilized the protein but had variable effects on the phosphatase activity and tumor growth. The magnitude of these effects was dependent on the presence of the COOH-terminal PEST sequences and on the cell type where the mutant proteins were expressed, suggesting the existence of fluctuating structural defects of the mutant protein. One of the C2 loop mutants induced a total loss of PTEN tumor-suppressor function, most likely by affecting both the membrane binding and the protein stability. These data support a double role for PTEN C2 domain in protein stability and in productive orientation of the catalytic site. |
| Keywords: | breast; mutational analysis; glioblastoma; cells; kinase; crystal-structure; endometrial; phosphatase-activity; pten/mmac1 gene; cowden-disease; lung-cancers |
| Journal Title: | Cancer Research |
| Volume: | 60 |
| Issue: | 24 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2000-12-15 |
| Start Page: | 7033 |
| End Page: | 7038 |
| Language: | English |
| ACCESSION: | WOS:000166201500047 |
| PROVIDER: | wos |
| PUBMED: | 11156408 |
| Notes: | Article -- Source: Wos |
Citation Impact
Related MSK Work