Journal of Biological Chemistry
Volume 278, Issue 33, 15 August 2003, Pages 30652-30660
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Mechanisms of Signal Transduction
Phosphorylation-regulated Cleavage of the Tumor Suppressor PTEN by Caspase-3: IMPLICATIONS FOR THE CONTROL OF PROTEIN STABILITY AND PTEN-PROTEIN INTERACTIONS*

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PTEN phosphatase is one of the most commonly targeted tumor suppressors in human cancers and a key regulator of cell growth and apoptosis. We have found that PTEN is cleaved by caspase-3 at several target sites, located in unstructured regions within the C terminus of the molecule. Cleavage of PTEN was increased upon TNFα-cell treatment and was negatively regulated by phosphorylation of the C-terminal tail of PTEN by the protein kinase CK2. The proteolytic PTEN fragments displayed reduced protein stability, and their capability to interact with the PTEN interacting scaffolding protein S-SCAM/MAGI-2 was lost. Interestingly, S-SCAM/MAGI-2 was also cleaved by caspase-3. Our findings suggest the existence of a regulatory mechanism of protein stability and PTEN-protein interactions during apoptosis, executed by caspase-3 in a PTEN phosphorylation-regulated manner.

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*

This work was supported in part by Grants PM1999-0039 and SAF2002-00085 from the Ministerio de Ciencia y Tecnología, by Grant CTIDIB-2002-86 from Generalitat Valenciana, Spain (to R. P.), and by National Institutes of Health Grants CA53840 and GM55989 (to N. K. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Recipient of a fellowship from Generalitat Valenciana, Spain and a Journal of Cell Science traveling fellowship. Present address: Keratinocyte Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

‡‡

Recipient of a postdoctoral fellowship from Bancaja, Spain.