MAP kinase phosphatases

The classical PTPs can be subdivided into receptorlike PTPs and nonreceptor, cytosolic PTPs. The second category of PTPs are broadly defined as dual specificity phosphatases (DSPs), which dephosphorylate pSer/ pThr as well as pTyr. MAP kinase phosphatases (MKPs) ( MAP kinase cascades) and PTEN are examples of DSP family members. Remarkably, PTEN also has lipid phosphatase activity that is specific for phosphatidylinositol-3,4,5-trisphosphate generated in response to the actions of PI3K. Finally, the class of low molecular mass (LM-) PTPs and that of CDC25 PTPs accomplish the cells repertoire of PTPs (Fig. 3). 

Keyse, S. M. An emerging family of dual specificity MAP kinase phosphatases. Biochim. Biophys. Acta 1265 152-160, 1995. 

Brondello, J. M. et al., Constitutive MAP kinase phosphatase (MKP-1) expression blocks... 

Bhalla, U. S., Ram, P. T., and Iyengar, R. (2002) MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018-1023. 

Figure 1 The MAPK pathway and its connections to other signals A negative feedback loop connects the phosphorylated endpoint of the pathway ERK (Extracellular-signal Regulated Kinase) to the transcriptionally-driven synthesis of the phosphatase, MKP MAP kinase phosphatase. MKP then de-phosphorylates ERK to shut down the signaling cascade. The positive feedback loop again starts with the terminal kinase ERK which activates cPLA2 (cytosolic phospholipase A2). This leads to the synthesis of arachidonic acid, which, in turn activates protein kinase C (PKC). PKC is a positive regulator of RAS (Please see Color Plate Section in the back of this book).

Nonn L, Duong D, Peehl DM. 2007. Chemopreventive anti-inflammatory activities of curcumin and other phytochcmicals mediated by MAP kinase phosphatase-5 in prostate cells. Carcinogenesis 28 1188-1196. 

Fig. 6.6 Signaling pathways involved in AlVmediated apoptosis. The stimulation of the AT2 receptor leads to a slow elevation in cellular ceramide, a proapoptotic messenger. The more rapid AT2 response results in the activation of a protein phosphatase, which has been identified as either a protein phosphatase 2A or MAP kinase phosphatase 1. The activated phosphatase catalyzes the dephosphorylation and inactivation of ERK1/2. Because ERK1/2 maintains the viability of Bcl-2, the inactivation of ERK1/2 leads to the dephosphorylation and degradation of the antiapoptotic factor.

Roessig, L., Hermann, C., Haendeler, J., Assmus, B., Zeiher, A.M., and Dimmeler, S. 2002. Angiotensin Il-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis. Basic Res. Cardiol. 97 1-8. 

Figure 11-2 Complex response of human cells to sub-lethal levels of nitric oxide. IMR-90 cells (normal, diploid human embryonic lung fibroblasts) were exposed to NO at 280 nM s" for 90 minutes, and then pulse-labeled for a further 90 minutes prior to two-dimensional gel analysis. The protein species listed (by Mr) behaved reprodudbly over several experiments. At least two dififeient control pathways operate in this induction transcriptional activation, as seen with CL-100, a MAP kinase phosphatase, and stabilization of mRNA, as found for HO-1 (see [35] for details). The induction of HO-1 and other activities by NO confers adaptive resistance to NO in rodent motor neurons [40],...

Chen, Y. S. Huang S. Lin-Shiau J. Lin. Bowman-Birk inhibitor abates proteasome function and suppresses the proliferation of MCF7 breast cancer cells through accumulation of MAP kinase phosphatase-1. Carcinogenesis, 200S, 26, 1296—1306. 

Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygai species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120(5) 649-661... 

Each MAPKK can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signaling. All members of the MAPK family require dual phosphorylation of a threonine and tyrosine residue within the catalytic domain by their respective upstream kinase in order to be activated. Hence ERK, JNK, and p38 contain ftie specific dual phosphorylation motif Thr-Glu-Tyr, Thr-Pro-Tyr, and Thr-Gly-Try, respectively [27], Besides the upstream kinases, the activation of MAPKs critically depends on fire activity of a special family of dual specificity phosphatases, the MAP kinase phosphatases (MKPs), which inactivate MAPK and therefore play an important role in the dynamics of MAPK signaling. 

Hutter D, Chen P, Barnes J, Liu Y. Catalytic activation of mitogen-activated protein (MAP) kinase phosphatase-1 by binding to p38 MAP kinase critical role of the p38 C-terminal domain in its negative regulation. Biochem J 2000 352 155-163. 

Zhou B, Wu L, Shen K, Zhang J, Lawrence DS, Zhang Z-Y. Multiple regions of MAP kinase phosphatase 3 are involved in its recognition and activation by ERK2. J Biol Chem 2001 276 6506-6515. 

Scimeca JC, Servant MJ, Dyer JO, Meloche S. Essential role of calciiun in the regulation of MAP kinase phosphatase-1 expression. Oncogene 1997 15 717-726. 

Burgun C, Esteve L, Humbolt N, Aunis D, Zwiller J. Cyclic AMP-elevating agents induce the expression of MAP kinase phosphatase-1 in PC12 cells. FEES Lett 2000 484 189-193. 

Boutros, T., Chevet E., and Metrakos, R (2008). Mitogen-activated protein (MAR) kinase/MAP kinase phosphatase regulation roles in cell growth, death, and cancer. Pharmacol. Rev. 60(3), 261-310. 

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