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Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C- Activation Requires CD82, Caveolin-1, and Ganglioside

¹ Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois and Departments of ² Biochemistry and ³ Oncology, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China

Requests for reprints: Amy S. Paller, Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, 676 North St. Clair Avenue, Suite 1600, Chicago, IL 60611. Phone: 312-695-3721; Fax: 312-695-0664; E-mail: apaller{at}northwestern.edu.

Activation of protein kinase C (PKC)- decreases normal and neoplastic cell proliferation by inhibiting epidermal growth factor receptor (EGFR)-related signaling. The molecular interactions upstream to PKC- that influence its suppression of EGFR, however, are poorly understood. We have found that caveolin-1, tetraspanin CD82, and ganglioside GM3 enable the association of EGFR with PKC-, ultimately leading to inhibition of EGFR signaling. GM3- and CD82-induced inhibition of EGFR signaling requires PKC- translocation and serine/threonine phosphorylation, which eventually triggers EGFR Thr⁶⁵⁴ phosphorylation and receptor internalization. Within this ordered complex of signaling molecules, the ability of CD82 to associate with PKC- requires the presence of caveolin-1, whereas the interaction of caveolin-1 or PKC- with EGFR requires the presence of CD82 and ganglioside GM3. Disruption of the membrane with methyl-ß-cyclodextrin dissociates the EGFR/GM3/caveolin-1/CD82/PKC- complex and prevents the inhibitory effect of PKC- on EGFR phosphorylation, suggesting that caveolin-1, CD82, and ganglioside interact with EGFR and PKC- within intact cholesterol-enriched membrane microdomains. Given the role of these membrane molecules in suppressing EGFR signaling, up-regulation of GM3, caveolin-1, and CD82 function may be an effective adjunctive therapy for treating epithelial cell malignancies. [Cancer Res 2007;67(20):9986–95]

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