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J. Biol. Chem., Vol. 283, Issue 8, 5127-5137, February 22, 2008

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Cdc42 Regulates E-cadherin Ubiquitination and Degradation through an Epidermal Growth Factor Receptor to Src-mediated Pathway^*

From the Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892

E-cadherins play an essential role in maintaining epithelial polarity by forming Ca²⁺-dependent adherens junctions between epithelial cells. Here, we report that Ca²⁺ depletion induces E-cadherin ubiquitination and lysosomal degradation and that Cdc42 plays an important role in regulating this process. We demonstrate that Ca²⁺ depletion induces activation of Cdc42. This in turn up-regulates epidermal growth factor receptor (EGFR) signaling to mediate Src activation, leading to E-cadherin ubiquitination and lysosomal degradation. Silencing Cdc42 blocks activation of EGFR and Src induced by Ca²⁺ depletion, resulting in a reduction in E-cadherin degradation. The role of Cdc42 in regulating E-cadherin ubiquitination and degradation is underscored by the fact that constitutively active Cdc42(F28L) increases the activity of EGFR and Src and significantly enhances E-cadherin ubiquitination and lysosomal degradation. Furthermore, we found that GTP-dependent binding of Cdc42 to E-cadherin is critical for Cdc42 to induce the dissolution of adherens junctions. Our data support a model that activation of Cdc42 contributes to mesenchyme-like phenotype by targeting of E-cadherin for lysosomal degradation.

Received for publication, April 19, 2007 , and in revised form, October 31, 2007.

^* 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.

¹ Both authors contributed equally to this work.

² An Interagency Oncology Task Force Fellow supported by the United States Food and Drug Administration and the NCI, National Institutes of Health, Bethesda, MD.

³ To whom correspondence should be addressed: Division of Monoclonal Antibodies, OBP/OPS/CDER/FDA, Bldg. 29B, Rm. 3NN-15, 29 Lincoln Dr., Bethesda, MD 20892-4555. Tel.: 301-827-0253; Fax: 301-827-0852; E-mail: wen.wu{at}fda.hhs.gov.

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