The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade.
Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) and MKP-2 are two members of a recently described family of dual specificity phosphatases that are capable of dephosphorylating p42/p44MAPK. Overexpression of MKP-1 or MKP-2 inhibits MAP kinase-dependent intracellular signaling events and fibroblast proliferation. By using specific antibodies that recognize endogenous MKP-1 and MKP-2 in CCL39 cells, we show that MKP-1 and MKP-2 are not expressed in quiescent cells, but are rapidly induced following serum addition, with protein detectable as early as 30 min (MKP-1) or 60 min (MKP-2). Serum induction of MKP-1 and MKP-2 is sustained, with protein detectable up to 14 h after serum addition. Induction of MKP-1 and, to a lesser extent, MKP-2 temporally correlates with p42/p44MAPK inactivation. To analyze the contribution of the MAP kinase cascade to MKP-1 and MKP-2 induction, we examined CCL39 cells transformed with either v-ras or a constitutively active direct upstream activator of MAP kinase, mitogen-activated protein kinase kinase-1 (MKK-1; MKK-1(SD/SD) mutant). In both cell models, MKP-1 and MKP-2 are constitutively expressed, with MKP-2 being prevalent. In addition, in CCL39 cells expressing an estradiol-inducible deltaRaf-1::ER chimera, activation of Raf alone is sufficient to induce MKP-1 and MKP-2. The role of the MAP kinase cascade in MKP induction was highlighted by the MKK-1 inhibitor PD 098059, which blunted both the activation of p42/p44MAPK and the induction of MKP-1 and MKP-2. However, the MAP kinase cascade is not absolutely required for the induction of MKP-1, as this phosphatase, but not MKP-2, was induced to detectable levels by agents that stimulate protein kinases A and C. Thus, activation of the p42/p44MAPK cascade promotes the induction of MKP-1 and MKP-2, which may then attenuate p42/p44MAPK-dependent events in an inhibitory feedback loop.
Brondello
J M
JM
Université de Nice, Centre de Biochimie, CNRS UMR 134, France.
Brunet
A
A
Pouysségur
J
J
McKenzie
F R
FR
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D018797:Cell Cycle Proteins; D000242:Cyclic AMP / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C / Q000378:metabolism; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism*; D013012:Sorbitol / Q000494:pharmacology
D018053:Arsenites; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D013012:Sorbitol; D003513:Cycloheximide; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; C517021:Dusp1 protein, rat; C094132:Dusp4 protein, rat; D017027:Protein Tyrosine Phosphatases; C015001:arsenite