Regulation of the Stress Activated MAP Kinase Cascades

One of the well-defined roles of PP2C in cell signaling is the downregulation of the stress-activated MAP kinase cascades in eukaryotes. A MAPK cascade is composed of three kinases: mitogen-activated protein kinase (MAPK), MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK). Extracellular stimuli are transmitted into the nucleus through sequential phosphorylation of these kinases; a signal-stimulated MAPKKK phosphorylates a specific MAPKK, which in turn phosphorylates the conserved threonine and tyrosine residues of its cognate MAPK [3]. Subsequently, an activated MAPK phosphorylates and activates nuclear transcription factors, inducing a set of genes for cellular responses. Consequently, dephosphorylation of any of the kinases in the cascade results in downregulation of the final outcome.

Studies in the budding yeast S. cerevisiae have shown that the multicopy expression of PP2C genes rescues the mutations that cause hyperactivation of the Hogl osmosensing MAPK cascade [4]. In the fission yeast S. pombe, inactiva-tion of the stress-activated MAPK Spcl (also known as Styl) suppresses the phenotypes of PP2C-deficient cells [5,6]. These genetic data suggested that PP2C phosphatases negatively regulate the MAPK pathways through dephosphoryla-tion of one or more components. Subsequent biochemical studies demonstrated that the fission yeast PP2C enzymes

Figure 1 Downregulation of the Spcl MAP kinase by PP2Cs. The Wisl MAPKK is activated by extracellular stress phosphorylate Thr-171 and Tyr-173 residues in the activation loop of the Spcl MAPK. Subsequently, activated Spcl phosphorylates downstream transcription factors, which in turn induce stress response genes as well as ptc1+ encoding a PP2C phosphatase. Ptcl dephosphorylates Spcl Thr-171 to inactivate the Spcl pathway. Ptc3, the other PP2C dephosphorylating Spcl, is expressed constitutively. Phosphorylation of Spcl Tyr-173 is negatively regulated by two tyrosine-specific phosphatases, Pypl and Pyp2.

Figure 1 Downregulation of the Spcl MAP kinase by PP2Cs. The Wisl MAPKK is activated by extracellular stress phosphorylate Thr-171 and Tyr-173 residues in the activation loop of the Spcl MAPK. Subsequently, activated Spcl phosphorylates downstream transcription factors, which in turn induce stress response genes as well as ptc1+ encoding a PP2C phosphatase. Ptcl dephosphorylates Spcl Thr-171 to inactivate the Spcl pathway. Ptc3, the other PP2C dephosphorylating Spcl, is expressed constitutively. Phosphorylation of Spcl Tyr-173 is negatively regulated by two tyrosine-specific phosphatases, Pypl and Pyp2.

Ptcl and Ptc3 dephosphorylate the Spcl MAPK at Thr-171

[7], for which phosphorylation is essential for Spcl activity

[8]. Interestingly, the ptc1+ gene is transcriptionally induced by activation of the Spcl pathway, while the ptc3+ gene is expressed constitutively [9]. Thus, PP2C participates in suppressing the Spcl MAPK under normal growth conditions and in a negative feedback regulation of Spcl activated by stress (Fig. l). In budding yeast, a PP2C enzyme, Ptcl, dephosphorylates Thr-l73 of Hogl MAPK, the equivalent of Spcl Thr-l7l in fission yeast [l0].

PP2C regulation of stress MAPK cascades is also conserved in mammalian and plant systems. Mammalian cells have two stress-activated MAP kinases, p38 and JNK. PP2Ca inhibits both MAPK cascades by dephosphorylating p38 and its MAPKK, MKK6, as well as the SEKl MAPKK upstream of JNK [ll]. The p38 MAPK is also inactivated by a PP2C5 isoform, Wipl [l2]. Wipl is transcriptionally induced in a p53-dependent manner in response to a variety of stresses such as y-irradiation, ultraviolet irradiation, and H2O2. Moreover, Wipl induction depends on the p38 MAPK, which phospho-rylates and stimulates p53 in response to ultraviolet irradiation. Thus, like the Spcl MAPK and the Ptcl phosphatase in fission yeast, the mammalian p38 MAPK and Wipl PP2C5 form a negative feedback loop. Recently, Wipl-deficient mice have been generated that exhibit defects in reproductive organs, immune function, and cell-cycle control [l3]. In alfalfa plants, a stress-inducible PP2C, MP2C, was identified as a negative regulator of the stress-activated MAPK cascade [l4].

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