Inhibitory phosphorylation

An inhibitory phosphorylation of the tyrosine kinases Lck and Fyn is also important for signal transduction, and this is performed by Csk kinase. This phosphorylation takes place at the C-terminus of Lck and inhibits the kinase activity in a similar way to that already structurally illustrated for Src kinase (see 8.3.2). 

Inhibitory phosphorylations (e. g., Thrl4, Tyrl5 on CDKs, see Chapter 13, phosphorylation of Src-kinase, see Section 8.3.2)... 

Fig. 13.19 The Gt DNA damage checkpoint. DNA damage induces activation of the protein kinases ATM and ATR via reactions not illustrated in the figure. ATM and ATR phosphorylate and activate the protein kinases Chkl and Chk2 which phosphorylate and inactivate the protein phosphatase CDC25A. This phosphatase is required for removal of the inhibitory phosphorylations on T14 and Y15 of CDK2 and hence for G S-phase progression. CDC25A phosphorylation mediates ubiquitination and proteasomal degradation ofCDC25A. As a consequence, CDK2 retains its inhibitory phosphorylations and the cell arrests in Gl.

The T-cell specific transcription factor, NFAT is held in the cytosol through the presence of an inhibitory phosphorylated residue. Upon TCR-mediated calcium release, the calcineurin dephosphorylates NFAT, translocates to the nucleus. CsA and FK 506 have proved useful in identifying this pharmaceutically vulnerable step in immune cell signaling [70]. 

Zhang, J. and Piantadosi, C.A. 1992. Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J. Clin. Invest. 90 1193-1199 Zhang, C., Lambert, M.P, Bunch, C., Barber, K., Wade, W.S., Krafft, G.A. and Klein, W.L. 1994. Focal adhesion kinase expressed by nerve cell lines shows increased tyrosine phosphorylation in response to Alzheimer s AP peptide. J. Biol. Chem. 269 25247-25250 Zhang, R, Phiel, C.J., Spece, L., Gurvich, N. and Klein, PS. 2003. Inhibitory phosphorylation of glycogen synthase ldnase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J. Biol. Chem. 278 33067-33077... 

Potapova TA, Daum JR, Byrd KS, Gorbsky GJ. 2009. Fine tuning the cell cycle activation of the Cdkl inhibitory phosphorylation pathway durine mitotic exit. Mol Biol Cell 20(6) 1737-1748. 

Preimplantation mouse embryos depend on inhibitory phosphorylation of separase to prevent chromosome missegregation. Mol Cell Biol 29(6) 1498-1505. 

Hutchins JR, Dikovskaya D, Clarke PR. 2002. Dephosphorylation of the inhibitory phosphorylation site S287 in Xenopus Cdc25C by protein phosphatase-2A is inhibited by 14-3-3 binding. FEES Lett 528(1-3) 267-271. 

The activity of CDKs is tightly regulated by inhibitory phosphorylation and by inhibitory molecules. The inhibitory phosphorylation is mediated by the Weel and MYTl kinases (Park and Lee 2003). In addition, two classes of protein-based inhibitors the 1NK4 group such as pi6 or pi5 and the CIP/KIP class such as p21" or p27 may negatively regulate the activity of CDKs (Park and Lee 2003 Schwartz and Shah 2005). 

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