Inactivation of MAPKs occurs by dephosphorylation of the tyrosine and threonine residues by specific phosphatases. The mitogen activated protein kinase phosphatase (MKP) family are dual specificity phosphatases that are able to dephosphorylate both the tyrosine and threonine in the activation loop of MAPKs.294 There are at least ten distinct MKP family members that can be divided roughly into two groups: the inducible nuclear MKPs and the more constitutively expressed MKPs found primarily in the cytosol. Each MKP displays selectivity toward certain MAPK family members. MKP-1 is an inducible phosphatase that is thought to preferentially dephosphorylate p38 and JNK,295 yet in some cases it can also inactivate ERK.296 The promoter of MKP-1 contains several regulatory sites (AP-1, AP-2, CRE, E-Box) that are modulated by a variety of signaling pathways, leading to MKP-1 gene induction. MKP-1 is upregulated by many stimuli such as growth factors, stress, phorbol esters, vasoactive peptides, increased intracellular cAMP, and increased Ca2+.294,297 Because MKP-1 can suppress p38 and JNK signaling, up-regulation of MKP-1 has been shown to have an anti-apoptotic effect.298 Up-regulation of MKP-1 has also been observed in certain cancers, including pancreatic ductal cell adenocarcinoma.299 We have shown that following islet isolation, MKP-1 expression increases over the first 72 hours following isolation.263 This increase in MKP-1 coincides with the decrease in JNK phosphorylation and could therefore mediate negative feedback inhibition of the JNK pathway. MKP-1 up-regulation could also represent a survival signal by decreasing the sensitivity of the islet to apoptotic signals acting through p38 and JNK. As mentioned earlier, however, p38 activation also rises steadily with time in culture.263 Thus, the exact role of MKP-1 in islet survival is still unclear.
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