Protein kinase A mediates cAMP-induced tyrosine phosphorylation of the epidermal growth factor receptor.
An increase in the intracellular cAMP concentration induces tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) followed by activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In this report we demonstrate that these effects of cAMP are mediated via activation of protein kinase A (PKA). Chemical inhibition of PKA suppressed forskolin-induced EGFR tyrosine phosphorylation and ERK1/2 activation in PC12 cells. Furthermore, forskolin failed to induce significant tyrosine phosphorylation of the EGFR and ERK1/2 activation in PKA-defective PC12 cells. Forskolin-induced EGFR tyrosine phosphorylation was also observed in A431 cells and in membranes isolated from these cells. Phosphoamino acid analysis indicated that the recombinant catalytic subunit of PKA elicited phosphorylation of the EGFR on both tyrosine and serine but not threonine residues in A431 membranes. Together, our data indicate that activation of PKA mediates the effects of cAMP on the EGFR and ERK1/2. While PKA may directly phosphorylate the EGFR on serine residues, PKA-induced tyrosine phosphorylation of the EGFR occurs by an indirect mechanism.
Piiper
Albrecht
A
Department of Internal Medicine, University of Saarland, D-66421, Homburg/Saar, Germany. inapii@uniklinik-saarland.de
Lutz
Manfred P
MP
Cramer
Henning
H
Elez
Robert
R
Kronenberger
Bernd
B
Dikic
Ivan
I
Müller-Esterl
Werner
W
Zeuzem
Stefan
S
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D008566:Membranes / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D014443:Tyrosine / Q000737:chemistry
D005576:Colforsin; D014443:Tyrosine; D000242:Cyclic AMP; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases