Phosphorylation mitogen-activated protein kinase

Pestka, J. and Zhou H.R. Hck- and PKR-dependent mitogen-activated protein kinase phosphorylation and AP-1, C/EBP and NF-kB activation precedes deoxynivalenol-induced TNF-2 and MIP-2 expression. The Toxicologist 72, 121, 2003. 

Moon, Y., Pestka, J.J. (2003). Deoxyn rvalenol-induced mitogen activated protein kinase phosphorylation and IL-6 expression in mice suppressed hy fish oil. J. Nutr. Biochem. 14 717-26. 

D.Y. Kim, Y. Kam, S.K. Koo, C.O. Joe, Gating connexin 43 channels reconstituted in lipid vesicles by mitogen-activated protein kinase phosphorylation, J Biol Chem 274, 5581-5587 (1999). 

B.J. Wam-Cramer, P.D. Lampe, W.E, Kurata, M.Y. Kanemitsu, L.W. Loo, W. Eckhart, A.F. Lau, Characterization of the mitogen-activated protein kinase phosphorylation sites on the connexin-43 gap junction protein,./ Biol Chem 271,3779-3786 (1996). 

A critical site is Ser-505, the site phosphorylated by mitogen-activated protein kinase. Phosphorylation at this site increases the activity of the enzyme both in vitro and in vivo. However, other phosphorylation sites may also be involved in particular, Ser-727 may also have an important role in some cell systems [23]. The Ser-505 is located in a flexible loop that connects the C2 and catalytic domains (Fig. 9). It is possible that phosphorylation of this residue produces the optimum orientation of the two domains with respect to the membrane interface (S. Das, 2003). Overall, it is probable that the role of phosphorylation in translocation, membrane binding, and enzyme activation depends on the cell type and the nature of the stimulus [23]. 

In human breast and prostate cancer cell fines, retinoids have been shown to induce apoptosis via induction of p21/ WAF/cipl (Thompson et al., 1996 Li et al., 1996) and affect G1 cell cycle arrest through mitogen-activated protein kinase phosphorylation (Nakagawa et al., 2003). Zhang and Rosdahl (2005) demonstrated that expression of Idl protein decreased and that of pi6 protein increased in melanoma cell fines exposed to all-rntwr-RA, and suggested that these alterations may be involved in the observed apoptosis and cell cycle redistribution. 

Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate h3q)oxia-inducible factor 1 alpha (HIF-lalpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999 274 32631-32637. 

Mitogen activated protein kinase (MARK) cascades are three kinase modules activated by phosphorylation. The three kinase modules are composed of a MAPK, a MAPKK, and a MAPKKK. There are multiple members of each component of the MAPK cascade that are conserved from yeast to human. Activation of selective MAPK modules by specific stimuli regulates cell functions such as gene expression, adhesion, migration, differ entiation, and apoptosis. 

The biochemical mechanism of Mos action is not yet established. Mos has been found to phosphorylate cyclin B in vitro, and it is possible that this phosphorylation directly inhibits cyclin B proteolysis (Roy et al., 1990). However, such a direct effect of phosphorylation on cyclin B stability remains to be demonstrated, and it is alternatively possible that Mos inhibits (directly or indirectly) the proteolytic pathway responsible for cyclin B degradation. Mos has recently been found to stimulate mitogen-activated protein kinase (MAP kinase) in Xenopus oocytes,... 

Lali, F. V., Hunt, A. E., Turner, S. J., and Foxwell, B. M. (2000). The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independendy ofp38 mitogen-activated protein kinase. J. Biol. Chem. 275, 7395-7402. 

The kinases themselves can be arranged into phosphorylation cascades so that one kinase phosphorylates another, which, in turn, phos-phorylates another. This often leads to some funny names, such as MAP kinase kinase kinase. This means a mitogen-activated protein kinase that phosphorylates MAP kinase kinase. The activated MAP kinase kinase then phosphorylates and activates MAP kinase. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

Mitogen-activated protein kinase phosphatases are dual-function protein phosphatases. Just as the MAPK kinases (e.g. MEKs) are unique as dual-functioning kinases in that they phosphorylate MAPKs on threonine and tyrosine residues, there are unique dual-function ing protein phosphatases that reverse the phosphorylation and activation of MAPKs [43], Such MAPK phosphatases (MKPs) were first identified as a product of vaccinia virus (VH1) and later found in all eukaryotic cells. There are now numerous members of this VH1 family of dual-functioning protein phosphatases. 

The catalytic activity of cPLA2 is stimulated by phosphorylation catalyzed by the mitogen-activated protein kinase (MAPK) at Ser505. This modification stimulates enzyme activity only, indicating that translocation and phosphorylation are independent mechanisms of cPLA2 regulation [21]. 

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