Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that the alpha-subunit of heterotrimeric G13 protein induces either mitogenesis and neoplastic transformation or apoptosis in a cell-dependent manner. Here, we analyzed which signaling pathways are required for G alpha 13-induced mitogenesis or apoptosis using a novel mutant of G alpha 13. We have identified that in human cell line LoVo, the mutation encoding substitution of Arg260 to stop codon in mRNA of G alpha 13 subunit produced a mutant protein (G alpha 13-T) that lacks a COOH terminus and is endogenously expressed in LoVo cells as a polypeptide of 30 kDa. We found that G alpha 13-T lost its ability to promote proliferation and transformation but retained its ability to induce apoptosis. We found that full-length G alpha 13 could stimulate Elk1 transcription factor, whereas truncated G alpha 13 lost this ability. G alpha 13-dependent stimulation of Elk1 was inhibited by dominant-negative extracellular signal-regulated kinase (MEK) but not by dominant-negative MEKK1. Similarly, MEK inhibitor PD-98059 blocked G alpha 13-induced Elk1 stimulation, whereas JNK inhibitor SB-203580 was ineffective. In Rat-1 fibroblasts, G alpha 13-induced cell proliferation and foci formation were also inhibited by dominant-negative MEK and PD-98059 but not by dominant-negative MEKK1 and SB-203580. Whereas G alpha 13-T alone did not induce transformation, coexpression with constitutively active MEK partially restored its ability to transform Rat-1 cells. Importantly, full-length but not G alpha 13-T could stimulate Src kinase activity. Moreover, G alpha 13-dependent stimulation of Elk1, cell proliferation, and foci formation were inhibited by tyrosine kinase inhibitor, genistein, or by dominant-negative Src kinase, suggesting the involvement of a Src-dependent pathway in the G alpha 13-mediated cell proliferation and transformation. Importantly, truncated G alpha 13 retained its ability to stimulate apoptosis signal-regulated kinase ASK1 and c-Jun terminal kinase, JNK. Interestingly, the apoptosis induced by G alpha 13-T was inhibited by dominant-negative ASK1 or by SB-203580.
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PMID:G alpha 13-mediated transformation and apoptosis are permissively dependent on basal ERK activity. 1273 37

The membrane redistribution and phosphorylation of focal adhesion kinase (FAK) have been reported to be important for cell migration. We previously showed that Lysophosphatidic acid (LPA) induced FAK membrane redistribution and autophosphorylation in ovarian cancer SK-OV3 cells and the signaling pathway consisting of Gi-Ras-MEKK1 mediated LPA-induced FAK membrane redistribution but not FAK autophosphorylation. We also showed that the disruption of the Gi-Ras-MEKK1 pathway led to a significant reduction in LPA-stimulated cell migration. These findings raised the question of whether LPA-induced FAK autophosphorylation was required for LPA-stimulated cell migration and what signaling mechanism was involved in LPA-induced FAK autophosphorylation. In this study, we expressed the membrane anchored wild-type FAK (CD2-FAK) in SK-OV3 cells and found that the expression of CD2-FAK greatly rescued LPA-stimulated cell migration in Gi or Ras-inhibited cells. However, Gi inhibitor pertussis toxin or dominant-negative H-Ras still significantly inhibited LPA-stimulated cell migration in cells expressing the membrane anchored FAK containing a mutation in the autophosphorylation site [CD2-FAK(Y397A)]. These results suggest that FAK autophosphorylation plays a role in LPA-stimulated cell migration. With the aid of p115RhoGEF-RGS, G12 and G13 minigenes to inhibit G12/13, we found that the G12/13 pathway was required for LPA-induced FAK autophosphorylation and efficient cell migration. Moreover, LPA activated RhoA and Rho kinase (ROCK) in a G12/13-dependent manner and their activities were required for LPA-induced FAK autophosphorylation. However, Rho or ROCK inhibitors displayed no effect on LPA-induced FAK membrane redistribution although they abolished LPA-induced cytoskeleton reorganization. Our studies show that the G12/13-RhoA-ROCK signaling pathway mediates LPA-induced FAK autophosphorylation and contributes to LPA-stimulated cell migration.
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PMID:The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration. 1630 93