Involvement of Protein Kinase D1 in Signal Transduction from the Protein Kinase C Pathway to the Tyrosine Kinase Pathway in Response to Gonadotropin-releasing Hormone.
The receptor for gonadotropin-releasing hormone (GnRH) belongs to the G protein-coupled receptors (GPCRs), and its stimulation activates extracellular signal-regulated protein kinase (ERK). We found that the transactivation of ErbB4 was involved in GnRH-induced ERK activation in immortalized GnRH neurons (GT1-7 cells). We found also that GnRH induced the cleavage of ErbB4. In the present study, we examined signal transduction for the activation of ERK and the cleavage of ErbB4 after GnRH treatment. Both ERK activation and ErbB4 cleavage were completely inhibited by YM-254890, an inhibitor of Gq/11 proteins. Down-regulation of protein kinase C (PKC) markedly decreased both ERK activation and ErbB4 cleavage. Experiments with two types of PKC inhibitors, Gö 6976 and bisindolylmaleimide I, indicated that novel PKC isoforms but not conventional PKC isoforms were involved in ERK activation and ErbB4 cleavage. Our experiments indicated that the novel PKC isoforms activated protein kinase D (PKD) after GnRH treatment. Knockdown and inhibitor experiments suggested that PKD1 stimulated the phosphorylation of Pyk2 by constitutively activated Src and Fyn for ERK activation. Taken together, it is highly possible that PKD1 plays a critical role in signal transduction from the PKC pathway to the tyrosine kinase pathway. Activation of the tyrosine kinase pathway may be involved in the progression of cancer.
From the Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan higasa@med.u-ryukyu.ac.jp.
Sayomi
S
Higa-Nakamine
From the Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
Noriko
N
Maeda
From the Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
Seikichi
S
Toku
From the Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
Hideyuki
H
Yamamoto
D002460:Cell Line; D004789:Enzyme Activation; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D059748:Proteolysis; D066247:Receptor, ErbB-4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D007987:Gonadotropin-Releasing Hormone; C089212:protein kinase D; C587689:ERBB4 protein, human; D011505:Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4; D011493:Protein Kinase C
ErbB4; Fyn; G protein-coupled receptor (GPCR); GnRH; Src; extracellular signal-regulated kinase (ERK); protein kinase C (PKC); protein kinase D (PKD)