Tanaka K, Abe M, Sato Y
Department of Vascular Biology, Tohoku University, Sendai.
Jpn J Cancer Res. 1999 Jun;90(6):647-54. doi: 10.1111/j.1349-7006.1999.tb00796.x.
We examined the role of mitogen-activated protein (MAP) kinases in the signal transduction of basic fibroblast growth factor (bFGF)-mediated effects in endothelial cells (ECs). When MSS31 murine endothelial cells were stimulated with bFGF, three MAP kinase homologs, extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) 1, and p38 MAP kinase were activated. The inhibition of the ERK1/2 pathway with PD98059, a specific inhibitor of MEK1, or of the p38 MAP kinase pathway with SB203580, a specific inhibitor of p38 MAP kinase, abrogated bFGF-mediated tube formation by MSS31 cells in type I collagen gel. Tube formation in type I collagen gel requires proliferation and migration of these cells, and degradation of the extracellular matrix by these cells. Both PD98059 and SB203580 inhibited bFGF-stimulated DNA synthesis as well as migration of MSS31 cells. Cell migration requires cytoskeleton reorganization and cell adhesion. bFGF induced actin reorganization and vinculin assembly in the focal adhesion plaque, both of which were inhibited by SB203580 but not by PD98059. bFGF induced the expression of the transcription factor ETS-1 in MSS31 cells. ETS-1 is responsible for the expression of proteases as well as integrin beta 3 subunit in ECs, and converts ECs to invasive phenotype. PD98059 inhibited this induction of ETS-1, whereas SB203580 did not. These results indicate that ERK1/2 and p38 MAP kinase are requisite for the signal transduction of bFGF in ECs. The roles of these two MAP kinase homologs are not identical, but these kinases work in a coordinated fashion.
我们研究了丝裂原活化蛋白（MAP）激酶在内皮细胞（ECs）中碱性成纤维细胞生长因子（bFGF）介导效应的信号转导中的作用。当用bFGF刺激MSS31小鼠内皮细胞时，三种MAP激酶同源物，即细胞外信号调节激酶（ERK）1/2、c-Jun氨基末端激酶（JNK）1和p38 MAP激酶被激活。用MEK1的特异性抑制剂PD98059抑制ERK1/2途径，或用p38 MAP激酶的特异性抑制剂SB203580抑制p38 MAP激酶途径，可消除MSS31细胞在I型胶原凝胶中bFGF介导的管形成。I型胶原凝胶中的管形成需要这些细胞的增殖和迁移，以及这些细胞对细胞外基质的降解。PD98059和SB203580均抑制bFGF刺激的MSS31细胞的DNA合成以及迁移。细胞迁移需要细胞骨架重组和细胞黏附。bFGF诱导肌动蛋白重组和粘着斑中纽蛋白组装，二者均被SB203580抑制，但不被PD98059抑制。bFGF诱导MSS31细胞中转录因子ETS-1的表达。ETS-1负责ECs中蛋白酶以及整合素β3亚基的表达，并将ECs转变为侵袭性表型。PD98059抑制ETS-1的这种诱导，而SB203580则不能。这些结果表明，ERK1/2和p38 MAP激酶是ECs中bFGF信号转导所必需的。这两种MAP激酶同源物的作用并不相同，但这些激酶以协同方式发挥作用。
