Proline-rich tyrosine kinase

Fak (focal adhesion kinase) is expressed in most tissues and is evolutionary conserved across species. It is activated by integrin clustering and by stimulation of several G protein-coupled recqrtors and RTKs. Fak is associated with focal adhesions and regulates cell spreading and migration. The kinase is essential for embryonic development since the homozygote Fak knockout is embryonic lethal. Pyk2 (proline-rich tyrosine kinase 2), the second member of the Fak kinase family has a more restricted expression pattern (primarily neuronal and hematopoietic cells) and does not localize to focal adhesions. 

In addition, the phosphotyrosine moiety (Y402) on a proline-rich tyrosine kinase (PYK2, a NRPTK) can apparently compete with phosphoY527 for interaction with SH2 domain on Src and lead to Src activation. PYK2 is a member of the Fak family. It is highly expressed in the nervous system. Its activation depends on both cell adhesion and the presence of calcium or PKC activation. Therefore, certain G-protein-coupled receptors (GPCRs)... 

PD Parkinson s disease PYR proline-rich tyrosine kinase... 

Guo, C., Zheng, C., Martin-Padura, L, Bian, Z.C. and GuanJ-L., 1998, Differential stimulation of proline-rich tyrosine kinase 2 and mitogen-activated protein kinase by sphingosine 1-phosphate. Eur. J. Biochem. 257 403-408. 

Boutahar N, Guignandon A, Vico L, Lafage-Proust MH. 2004. Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase-2 tyrosine sites involved in ERK activation. J Biol Chem 279 30588-99. 

Fig. 6.4 Proposed scheme for ATj-mediated transactivation of the EGF receptor and the subsequent activation of ERK1/2. The interaction of angiotensin II with the ATi receptor stimulates several pathways that result in the transactivation of the EGF receptor. In one pathway, phospholipase C (PLC) is activated, which in turn promotes the production of reactive oxygen species (ROS). ATj receptor activation also elevates [Ca2+]j, contributing to the stimulation of a Ca2+-dependent tyrosine kinase, of which Src and proline-rich tyrosine kinase-2 (Pyk2) are the preferred targets. Both ROS and the Ca2+-dependent tyrosine kinase activate a metalloprotease, presumably ADAM17, which proteolytically activates the EGF ligand. The Ca2+-dependent tyrosine kinase, as well as a Ca2+-independent kinase, also phosphorylate the EGF receptor. The activation of the EGF receptor triggers a cascade leading to the activation of ERK1/2. EGF receptor transactivation also proceeds via a G-protein-independent pathway (see text).

Wang, D., Yu, X., and Brecher, P. 1999. Nitric oxide inhibits angiotensin II-induced activation of the calcium-sensitive tyrosine kinase proline-rich tyrosine kinase 2 without affecting epidermal growth factor receptor transactivation. J. Biol. Chem. 274 24342-24348. 

Shah BH, Catt KJ. 2002. Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Mol Pharmacol 61 343-351. 

Chieffi P, Barchi M, Di Agostino S, Rossi P, Tramontano D, Geremia R. 2003. Prolin-rich tyrosine kinase 2 (PYK2) expression and localization in mouse testis. Mol Reprod Dev 65(3) 330-335. 

CaMK kinases are Ca2+/calmodulin regulated kinases, while CMGC Pks collect cyclic-dependent, mitogene-activated peptide (MAP) kinases, GSK3 and Clk kinases, that phosphorylate substrates in proline-rich domains. The last group are PTKs (protein tyrosine kinases), which include both receptor and non-receptor kinases, which phosphorylates tyrosine residues (this will be discussed in Sect. 4.3). 

A more detailed picture of the folding of the SH3 (Src homology 3) domain of the Fyn protein kinase has been obtained by relaxation dispersion experiments.93 9 SFI3 domains bind proline-rich sequences and are key components of proteins involved in protein tyrosine kinase signalling pathways. The folding of the SFI3 domain of the Fyn protein kinase has been extensively characterized by stopped-flow and NMR experiments. CPMG relaxation dispersion analysis revealed that the Fyn SH3 domain is essentially a three-state folder with an intermediate state. 

Fig. 3.3 The structure of the N-terminal SH3 domain of Grb2 bound to a proline-rich Sos peptide has been determined by NMR.29.30 The structure of the Gbr2 N-terminal SH3 domain, compiexed with a 10-residue peptide, comprising residues 1134-1144 (VPPPVPPRRR-NHz) of Sos, is shown. The prolyl residues, P2, P3, P6, and P7, which interact with the SH3 domain of Grb2 are marked. (The ribbon model was reproduced with permission of the authors and J. Mol. Biol, from data in ref. 30, available In databanks.) A variation of this scheme is the recognition of a proline-rich sequence (APTMPPPLPP) in the GAP protein for Rho by the SH3-domain of the cytosolic c-Abi tyrosine kinase. i This interaction couples the Rho/GAP tightly to this cytosolic tyrosine kinase and brings the momomeric G protein, Rho, under the control of phosphorylation by the kinase.

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