Suppression of epidermal growth factor receptor signaling by protein kinase C-alpha activation requires CD82, caveolin-1, and ganglioside.
Activation of protein kinase C (PKC)-alpha decreases normal and neoplastic cell proliferation by inhibiting epidermal growth factor receptor (EGFR)-related signaling. The molecular interactions upstream to PKC-alpha 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-alpha, ultimately leading to inhibition of EGFR signaling. GM3- and CD82-induced inhibition of EGFR signaling requires PKC-alpha 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-alpha requires the presence of caveolin-1, whereas the interaction of caveolin-1 or PKC-alpha with EGFR requires the presence of CD82 and ganglioside GM3. Disruption of the membrane with methyl-beta-cyclodextrin dissociates the EGFR/GM3/caveolin-1/CD82/PKC-alpha complex and prevents the inhibitory effect of PKC-alpha on EGFR phosphorylation, suggesting that caveolin-1, CD82, and ganglioside interact with EGFR and PKC-alpha 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.
Wang
Xiao-qi
XQ
Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA, and Department of Biochemistry, The First Affiliated Hospital, Dalian, Liaoning, China.
Yan
Qiu
Q
Sun
Ping
P
Liu
Ji-Wei
JW
Go
Linda
L
McDaniel
Shauntae M
SM
Paller
Amy S
AS
D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005679:G(M3) Ganglioside / Q000378:metabolism*; D006801:Humans; D051861:Kangai-1 Protein / Q000378:metabolism*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D015398:Signal Transduction
C495540:CAV1 protein, human; D051242:Caveolin 1; D005679:G(M3) Ganglioside; D051861:Kangai-1 Protein; D002784:Cholesterol; D066246:ErbB Receptors; D051571:Protein Kinase C-alpha