P21-activated kinase

A second family of MAPKs is referred to as stress-activated protein kinases (SAPKs) [3,14,15]. This includes JNKs, or Jun kinases, named originally for their phosphorylation of the transcription factor c-Jun. SAPKs were first identified in peripheral tissues on the basis of their activation in response to cellular forms of stress, which include X-ray irradiation and osmotic stress. More recently, they have been demonstrated to be activated in brain by several cytokines as well as by synaptic activity [16]. As shown in Figure 23-3, SAPKs are activated by SAPK kinases (SEKs), which are in turn activated by SEK kinases. The Ras-like small G proteins implicated in SEK kinase activation are Rac and Cdc-42. In this case, it appears that Rac/Cdc-42 triggers activation of SEK kinase by stimulating its phosphorylation by still another protein kinase termed p21-activated kinase (PAK). Thus, PAK can be considered a MAPK kinase kinase kinase, which is analogous to the cascade of protein kinases found in yeast (Fig. 23-4). 

Activation of MEK kinases occurs particularly via proteins of the Ras superfamUy (p21-Ras, Rho/Rac proteins). However, other pathways for activation of MEK kinases, e.g., via other protein kinases such as protein kinase C or PAK (p21 activated kinase) (review Marshall, 1995 Robinson and Cobb, 1997) have also been reported. 

Cytoskeleton deregulation gelsolin, focal adhesion kinase (FAK), p21-activated kinase (PAK)... 

Sanders, L.C. Matsumura, F. Bokoch, G.M. de Lanerolle, P. Inhibition of myosin light chain kinase by p21-activated kinase. Science, 283, 2083-2085 (1999)... 

Lee, S.R Mahasneh, A. de la Roche, M. Cote, G.P. Regulation of the p21-activated kinase-related Dictyostelium myosin I heavy chain kinase by autophosphorylation, acidic phospholipids, and Ca " -calmodulin. J. Biol. Chem., 273, 27911-27917 (1998)... 

Brzeska, H. Young, R. Tan, C. Szczepanowska, J. Korn, E.D. Calmodulinbinding and autoinhibitory domains of Acanthamoeba myosin I heavy chain kinase, a p21-activated kinase (PAK). J. Biol. Chem., 276, 47468-47473 (2001)... 

Barac, A., Basile, J., Vazquez-Prado, J., Gao, Y., Zheng, Y., and Gutkind, J. S. (2004). Direct interaction of p21-activated kinase 4 with PDZ-RhoGEF, a G protein-linked Rho guanine exchange factor. J. Biol. Chem. 279, 6182-6189. 

Bokoch GM (2003) Biology of the p21-activated kinases. Annu Rev Biochem 72 743-781 Bredt DS, NicoU RA (2(X)3) AMPA receptor trafficking at excitatory synapses. Neuron 40 361—379 Chahrour M, Zoghbi HY (2007) The story of Rett syndrome from clinic to neurobiology. Neuron 56 422-437... 

Daniels RH, Zenke FT, Bokoch GM (1999) Alphapix stimulates p21-activated kinase activity through exchange factor-dependent and -independent mechanisms. J Biol Chem 274 6047-6050... 

Jaffer ZM, Chemoff J (2002) p21-activated kinases three more join the Pak. Int J Biochem Cell Biol 34 713-717... 

Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Erautschy SA, Cole GM (2006) Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 9 234-242... 

Kiosses WB, Daniels RH, Otey C, Bokoch GM, Schwartz MA. A role for p21-activated kinase in endothelial cell migration. J. CeU. Biol. 1999 147 831-844. 

Other protein kinases (OPK) These kinases fall outside of the major groups. They include the MEK/Ste7p family, p21-activated kinase (PAK)/Ste 20p family, MEKK/Stellp family, the Raf family, the activin/TGPP receptor family, the flowering plant putative receptor kinase family, the casein kinase I family and the LIM kinases (I IMKs). The members of the first four families function in the MAPK family... 

Examples include the focal adhesion kinase FAK (see Section 11.3), P-catenin (see Section 14.9), p21-activated kinase (PAK), replication factor C, and poly-ADP-ribose polymerase. The latter enzyme participates in the repair of DNA double-strand breaks. 

The NF2 gene is a tumor suppressor on chromosome 22. Loss of expression of the NF2 protein product, Merlin (Schwannomin), is associated with both sporadic and NF2-related schwannomas.Merlin is a cytoskeleton-associated tumor suppressor protein regulated by phosphorylation at serine 518 (S518). Unphosphorylated Merlin restricts cell proliferation by inhibiting Rac and p21-activated kinase (Pak). In Merlin-deficient schwannoma cells, Rac causes nonfunctional intercellular adhesion in aggregation assays that could cause increased proliferation rates owing to loss of contact inhibition. 1 ... 

Thaxton C, Lopera J, Bott M, et al. Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways. Oncogene. 2008 27 2705-2715. 

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