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Cross‐talk between epidermal growth factor receptor and protein kinase C during calcium‐induced differentiation of keratinocytes
Author(s) -
Denning M. F.,
Dlugosz A. A.,
Cheng C.,
Dempsey P. J.,
Coffey Jr R. J.,
Threadgill D. W.,
Magnuson T.,
Yuspa S. H.
Publication year - 2000
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1034/j.1600-0625.2000.009003192.x
Subject(s) - tyrosine phosphorylation , protein kinase c , phosphorylation , microbiology and biotechnology , keratinocyte , tyrosine kinase , receptor tyrosine kinase , platelet derived growth factor receptor , biology , signal transduction , protein tyrosine phosphatase , chemistry , cancer research , receptor , growth factor , biochemistry , in vitro
The induction of epidermal differentiation by extracellular Ca 2+ involves activation of both tyrosine kinase and protein kinase C (PKC) signaling cascades. To determine if the differentiation‐dependent activation of tyrosine kinase signaling can influence the PKC pathway, we examined the tyrosine phosphorylation status of PKC isoforms in primary mouse keratinocytes stimulated to terminally differentiate with Ca 2+ . Elevation of extracellular Ca 2+ induced tyrosine phosphorylation of PKC‐δ, but not the other keratinocyte PKC isoforms (α,ε, η, ζ). We have previously demonstrated that activation of the epidermal growth factor receptor (EGFR) pathway induces PKC‐δ tyrosine phosphorylation in basal keratinocytes (Denning M F, Dlugosz A A, Threadgill D W, Magnuson T, Yuspa S H (1996) J Biol Chem 271: 5325–5331). When basal keratinocytes were stimulated to differentiate by Ca 2+ , the level of cell‐associated transforming growth factor‐α (TGF‐α) increased 30‐fold, while no increase in secreted TGF‐α was detected. Furthermore, Ca 2+ ‐induced tyrosine phosphorylation of PKC‐δ and phosphotyrosine‐association of the receptor adapter protein Shc was diminished in EGFR −/− keratinocytes, suggesting that EGFR activation may occur during keratinocyte differentiation. Tyrosine phosphorylated PKC‐δ was also detected in mouse epidermis, suggesting that this differentiation‐associated signaling pathway is physiological. These results establish a requirement for the EGFR in Ca 2+ ‐induced tyrosine phosphorylation of PKC‐δ, and document the production of cell‐associated TGF‐α in differentiated keratinocytes which may function independent of its usual mitogenic effects.