Role of Dbl's big sister in the anti-mitogenic pathway from alpha1B-adrenergic receptor to c-Jun N-terminal kinase.
We previously reported that the alpha1B-adrenergic receptor leads to activation of Rho family small GTPases, and in turn, c-Jun N-terminal kinase (JNK), which results in the inhibition of cell proliferation. Here, we show the involvement of the Rho family guanine nucleotide exchange factor (GEF) Dbl's Big Sister (Dbs) in the signaling pathway. Transfection of a Dbl-homology (DH) and pleckstrin-homology (PH) domain-deficient form of Dbs into cells blocked the alpha1B-adrenergic receptor-induced activation of JNK. Conversely, transfection of an isolated DH domain of Dbs induced JNK activation. Stimulation of the alpha1B-adrenergic receptor enhanced an intrinsic Cdc42-GEF activity of Dbs in a manner dependent on Src family tyrosine kinases. Additionally, DH and PH domain deficient Dbs blocked the receptor-induced inhibition of cell proliferation, while DH domain of Dbs inhibited cell proliferation via the JNK-dependent pathway. Taken together, Dbs may play an important role in the anti-mitogenic JNK pathway downstream of the alpha1B-adrenergic receptor.
Yamauchi
Junji
J
Department of Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, 630-0101, Nara, Japan.
Hirasawa
Akira
A
Miyamoto
Yuki
Y
Kokubu
Hiroshi
H
Nishii
Hiroko
H
Okamoto
Miyuki
M
Sugawara
Yo
Y
Tsujimoto
Gozoh
G
Itoh
Hiroshi
H
D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
C547717:Adra1b protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C092132:Mcf2l protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D064067:Rho Guanine Nucleotide Exchange Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein