Yamauchi J, Tsujimoto G, Kaziro Y, Itoh H
Department of Molecular Cell Pharmacology, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-1809, the Japan.
J Biol Chem. 2001 Jun 29;276(26):23362-72. doi: 10.1074/jbc.M011752200. Epub 2001 Apr 13.
Heterotrimeric G protein G(q) stimulates the activity of p38 mitogen-activated protein kinase (MAPK) in mammalian cells. To investigate the signaling mechanism whereby alpha and betagamma subunits of G(q) activate p38 MAPK, we introduced kinase-deficient mutants of mitogen-activated protein kinase kinase 3 (MKK3), MKK4, and MKK6 into human embryonal kidney 293 cells. The activation of p38 MAPK by Galpha(q) and Gbetagamma was blocked by kinase-deficient MKK3 and MKK6 but not by kinase-deficient MKK4. In addition, Galpha(q) and Gbetagamma stimulated MKK3 and MKK6 activities. The MKK3 and MKK6 activations by Galpha(q), but not by Gbetagamma, were dependent on phospholipase C and c-Src. Galpha(q) stimulated MKK3 in a Rac- and Cdc42-dependent manner and MKK6 in a Rho-dependent manner. On the other hand, Gbetagamma activated MKK3 in a Rac- and Cdc42-dependent manner and MKK6 in a Rho-, Rac-, and Cdc42-dependent manner. Gbetagamma-induced MKK3 and MKK6 activations were dependent on a tyrosine kinase other than c-Src. These results suggest that Galpha(q) and Gbetagamma stimulate the activity of p38 MAPK by regulating MKK3 and MKK6 through parallel signaling pathways.
异源三聚体G蛋白G(q)可刺激哺乳动物细胞中p38丝裂原活化蛋白激酶（MAPK）的活性。为了研究G(q)的α和βγ亚基激活p38 MAPK的信号传导机制，我们将丝裂原活化蛋白激酶激酶3（MKK3）、MKK4和MKK6的激酶缺陷型突变体导入人胚肾293细胞。Gα(q)和Gβγ对p38 MAPK的激活被激酶缺陷型MKK3和MKK6阻断，但未被激酶缺陷型MKK4阻断。此外，Gα(q)和Gβγ刺激了MKK3和MKK6的活性。Gα(q)而非Gβγ对MKK3和MKK6的激活依赖于磷脂酶C和c-Src。Gα(q)以Rac和Cdc42依赖的方式刺激MKK3，以Rho依赖的方式刺激MKK6。另一方面，Gβγ以Rac和Cdc42依赖的方式激活MKK3，以Rho、Rac和Cdc42依赖的方式激活MKK6。Gβγ诱导的MKK3和MKK6激活依赖于除c-Src之外的一种酪氨酸激酶。这些结果表明，Gα(q)和Gβγ通过平行信号通路调节MKK3和MKK6来刺激p38 MAPK的活性。
