title: Role of Dbl's big sister in the anti-mitogenic pathway from alpha1B-adrenergic receptor to c-Jun N-terminal kinase.
abstract: 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.
authors.affiliation: Department of Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, 630-0101, Nara, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kokubu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nishii
authors.forename: Miyuki
authors.initials: M
authors.lastname: Okamoto
authors.forename: Yo
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: 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
chemical_list: 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