Related kinases protein kinase family

The neurotrophin receptor p75 was first identified as a nerve growth factor (NGF)-binding protein and was subsequently shown to interact with each of the other neurotrophic factors, BDNF, neurotrophin-3, and neurotrophin-4/-5. It also modulates the activity of several members of the tropomyosin-related receptor tyrosine kinase family (Trk) (reviewed in Chao, 2003). p75, a member of the tumor necrosis factor superfamily, is a type I transmembrane protein with four cysteine-rich domains in its extracellular region and a Death domain in its cytoplasmic protein (Fig. 11). 

Becker, W. Weber, Y. Wetzel, K. Eirmbter, K. Tejedor, F.J. Joost, H.G. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J. Biol. Chem., 273, 25893-25902 (1998)... 

The polypeptide chain of Src tyrosine kinase, and related family members, comprises an N-terminal "unique" region, which directs membrane association and other as yet unknown functions, followed by a SH3 domain, a SH2 domain, and the two lobes of the protein kinase. Members of this family can be phosphorylated at two important tyrosine residues—one in the "activation loop" of the kinase domain (Tyr 419 in c-Src), the other in a short... 

The best characterized family of MAPKs in the brain are the extracellular signal-regulated protein kinases (ERKs) that are activated by the neurotrophins and related growth factors (Fig. 23-4) [14,15]. The MAPK kinases responsible... 

Protein kinase C (PKC) exists as a family of closely related kinase subspecies with a heterogeneous distribution in the brain 897... 

SI39 (for mammals). The responsible kinases are members from phosphatidyli-nositol 3-kinase (PI3K)-like family kinases, which include ataxia telangiectasia mutated (ATM), AT-related (ATR), and DNA dependent protein kinase (DNA-PK) (Burma et al, 2001 Stiff et al, 2004 van Attikum and Gasser, 2005). Histone H2AX phosphorylation is directly related to repair of damaged chromatin (for details see chapter on Role of histone phosphorylation in chromatin dynamics and its implication in diseases ). 

Fig. 15.9. Antiapoptotic signalling by the PI3-kinase/Akt kinase pathway The PI3 kinase/Akt kinase pathway influences apoptosis via phosphorylation of the Bad protein, which is a member of the family of Bcl-2 proteins. Activation of the PI3-kinase pathway leads to Akt-kinase-catalyzed phosphorylation of Bad protein. Bad protein in its unphosphorylated form participates in activation of initiator caspases and thus has a proapoptotic effect. Phosphorylation of Bad protein by Akt kinase (or related kinases) has an antiapoptotic effect since phosphoryla-ted Bad protein is a binding substrate of 14-3-3 proteins. Bad is thus sequestered in an inactive state and is not available for triggering of apoptosis.

The probes of this type were shown to selectively label at least 75% of human kinases in crude cell lysates, thus demonstrating their selectivity and promiscuity for kinases [101]. As a follow up, the labeled kinases were subjected to proteolytic digestion, and the biotinylated peptides purified on avidin beads and analyzed by LC-MS/MS. This analysis demonstrated that the site of probe labeling was indeed the conserved active-site lysine as predicted. In contrast to the promiscuity demonstrated by the acyl phosphate probes, several selective covalent inhibitors of protein kinases have been used as ABPP probes. Wortmannin is a natural product derived from the fungus Penicillium funiculosum. It is a potent and specific covalent inhibitor of phosphoinositide 3-kinase (PI3K) and the PI3K-related kinase (PIKK) families [102, 103]. The use of natural products in relation to ABPP is covered by Breinbauer et al. [104]. 

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