Cuevas Bruce D, Abell Amy N, Witowsky James A, Yujiri Toshiaki, Johnson Nancy Lassignal, Kesavan Kamala, Ware Marti, Jones Peter L, Weed Scott A, DeBiasi Roberta L, Oka Yoshitomo, Tyler Kenneth L, Johnson Gary L
Department of Pharmacology, Craniofacial Biology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
EMBO J. 2003 Jul 1;22(13):3346-55. doi: 10.1093/emboj/cdg322.
Herein, we define how MEKK1, a MAPK kinase kinase, regulates cell migration. MEKK1 is associated with actin fibers and focal adhesions, localizing MEKK1 to sites critical in the control of cell adhesion and migration. EGF-induced ERK1/2 activation and chemotaxis are inhibited in MEKK1-/- fibroblasts. MEKK1 deficiency causes loss of vinculin in focal adhesions of migrating cells, increased cell adhesion and impeded rear-end detachment. MEKK1 is required for activation of the cysteine protease calpain and cleavage of spectrin and talin, proteins linking focal adhesions to the cytoskeleton. Inhibition of ERK1/2 or calpain, but not of JNK, mimics MEKK1 deficiency. Therefore, MEKK1 regulates calpain-mediated substratum release of migrating fibroblasts.
在此，我们阐述了丝裂原活化蛋白激酶激酶激酶1（MEKK1）如何调节细胞迁移。MEKK1与肌动蛋白纤维和粘着斑相关，将MEKK1定位于对细胞粘附和迁移控制至关重要的位点。在MEKK1基因敲除的成纤维细胞中，表皮生长因子（EGF）诱导的细胞外信号调节激酶1/2（ERK1/2）激活和趋化性受到抑制。MEKK1缺乏导致迁移细胞粘着斑中纽蛋白丢失，细胞粘附增加且后端脱离受阻。MEKK1是半胱氨酸蛋白酶钙蛋白酶激活以及血影蛋白和踝蛋白裂解所必需的，这些蛋白将粘着斑与细胞骨架相连。抑制ERK1/2或钙蛋白酶，而非c-Jun氨基末端激酶（JNK），可模拟MEKK1缺乏的情况。因此，MEKK1调节钙蛋白酶介导的迁移成纤维细胞与基质的脱离。
