Hedges J C, Dechert M A, Yamboliev I A, Martin J L, Hickey E, Weber L A, Gerthoffer W T
Cell and Molecular Biology Program, University of Nevada at Reno, Reno, Nevada 89557-0046, USA.
J Biol Chem. 1999 Aug 20;274(34):24211-9. doi: 10.1074/jbc.274.34.24211.
Smooth muscle cells are exposed to growth factors and cytokines that contribute to pathological states including airway hyperresponsiveness, atherosclerosis, angiogenesis, smooth muscle hypertrophy, and hyperplasia. A common feature of several of these conditions is migration of smooth muscle beyond the initial boundary of the organ. Signal transduction pathways activated by extracellular signals that instigate migration are mostly undefined in smooth muscles. We measured migration of cultured tracheal myocytes in response to platelet-derived growth factor, interleukin-1beta, and transforming growth factor-beta. Cellular migration was blocked by SB203580, an inhibitor of p38(MAPK). Time course experiments demonstrated increased phosphorylation of p38(MAPK). Activation of p38(MAPK) resulted in the phosphorylation of HSP27 (heat shock protein 27), which may modulate F-actin polymerization. Inhibition of p38(MAPK) activity inhibited phosphorylation of HSP27. Adenovirus-mediated expression of activated mutant MAPK kinase 6b(E), an upstream activator for p38(MAPK), increased cell migration, whereas overexpression of p38alpha MAPK dominant negative mutant and an HSP27 phosphorylation mutant blocked cell migration completely. The results indicate that activation of the p38(MAPK) pathway by growth factors and proinflammatory cytokines regulates smooth muscle cell migration and may contribute to pathological states involving smooth muscle dysfunction.
平滑肌细胞会接触到多种生长因子和细胞因子，这些因子会导致包括气道高反应性、动脉粥样硬化、血管生成、平滑肌肥大和增生在内的病理状态。其中几种病症的一个共同特征是平滑肌迁移超出了器官的初始边界。在平滑肌中，由促使迁移的细胞外信号激活的信号转导途径大多尚不明确。我们检测了培养的气管肌细胞对血小板衍生生长因子、白细胞介素-1β和转化生长因子-β的迁移反应。细胞迁移被p38（丝裂原活化蛋白激酶）的抑制剂SB203580阻断。时间进程实验表明p38（丝裂原活化蛋白激酶）的磷酸化增加。p38（丝裂原活化蛋白激酶）的激活导致热休克蛋白27（HSP27）磷酸化，这可能会调节F-肌动蛋白聚合。抑制p38（丝裂原活化蛋白激酶）活性会抑制HSP27的磷酸化。腺病毒介导的p38（丝裂原活化蛋白激酶）的上游激活剂——活化突变型丝裂原活化蛋白激酶激酶6b（E）的表达增加了细胞迁移，而p38α丝裂原活化蛋白激酶显性负突变体和HSP27磷酸化突变体的过表达则完全阻断了细胞迁移。结果表明，生长因子和促炎细胞因子激活p38（丝裂原活化蛋白激酶）途径可调节平滑肌细胞迁移，并可能导致涉及平滑肌功能障碍的病理状态。
