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Protein kinase C (PKC)eta-mediated PKCmu activation modulates ERK and JNK signal pathways

 
: Brändlin, I.; Hübner, S.; Eiseler, T.; Martinez-Moya, M.; Horschinek, A.; Hausser, A.; Link, G.; Rupp, S.; Storz, P.; Pfizenmaier, K.; Johannes, F.-J.

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The Journal of biological chemistry 277 (2002), No.8, pp.6490-6496
ISSN: 0021-9258
ISSN: 1083-351X
English
Journal Article
Fraunhofer IGB ()

Abstract
Protein kinase C (PKC), a family of lipid-activated serine kinases, is involved in multiple functions in the regulation of growth control. The PKC-related isoform PKCmu/PKD has been implicated in mitogenic signal cascades because of the activation of p42/p44 MAPK leading to Elk1-mediated gene transcription, and PKCmu/PKD has been shown to be activated via a PKC-dependent pathway. By using confocal analyses, we demonstrate here that PKCmu partially colocalizes with PKC-eta in different cell types. Colocalization depends on the presence of the PKCmu pleckstrin homology domain. Coexpression of constitutively active PKC-eta with PKCmu leads to a significant enhancement of the PKCmu substrate phosphorylation capacity as a result of an increased phosphorylation of the activation loop Ser(738/742) of PKCmu, whereas Ser(910) autophosphorylation remains unaffected. In vitro phosphorylation experiments show that PKCeta directly phosphorylates PKCmu on activation loop serines. Consequently, the p42 MAPK cascade is triggered leading to an increase in reporter gene activity driven by a serum-responsive element in HEK293 cells. At the same time, PKCeta-mediated JNK activation is reduced, providing evidence for a mutual regulation of PKCmu/PKCeta affecting different arms of the p38/ERK/ JNK pathways. Our data provide evidence for the sequential involvement of selective PKC isoforms in kinase cascades and identify the relevant domains in PKCmu for interaction with and activation by PKCeta as pleckstrin homology domain and activation loop.

: http://publica.fraunhofer.de/documents/N-26129.html