Nonreceptor Tyrosine Kinase Activation

8.1. Src Family Kinases

To date at least 14 Src kinase family members have been identified, of which the 60-kDa c-Src is ubiquitously expressed. All Src family members share common functional domains, including an N-terminal myristoylation sequence for membrane targeting, SH2 and SH3 domains for protein binding, a kinase domain and a C-terminal noncatalytic domain (82). c-Src is abundantly expressed in cardiomyocytes and VSMC and is rapidly activated by Ang II (83). Src has an important role in Ang II-induced phosphorylation of PLC-y and IP3 formation. Src, intracellular Ca2+ and PKC regulate Ang II-induced phosphorylation of p130Cas, a signaling molecule involved in integrin-mediated cell adhesion. Src has also been associated with Ang II-induced activation of Pyk2 and extracellular signal-regulated kinases (ERKs), as well as the activation of other downstream proteins including FAK, paxillin, JAK2, signal transducer and activator of transcription (STAT)-1, caveolin, and the adapter protein, Shc (84). Activation of c-Src is required for cytoskeletal reorganization, focal adhesion formation, and cell migration

Pdgfrb Stat3

Fig. 3. Novel signal transduction mechanisms mediated by ATj. Ang II phosphorylates multiple tyrosine kinases, such as JAK, FAK, Pyk2, p130Cas, and PI3K. Activated tyrosine kinases phosphorylate many downstream targets including the MAP kinase cascade. Src associates with the adapter protein complex, Shc-GRB2-Sos, that induces guanine nucleotide exchange on the small G protein Ras-GDP/GTP. Activated Ras-GTP interacts with Raf, resulting in phosphorylation of MEK, which in turn, phosphorylates MAP kinases, including ERK1/2, JNK/SAPK, and p38. Rho is also activated through ATi receptors. In addition, Ang II influences activity of receptor tyrosine kinases (RTK), such as EGFR, and PDGFR. The transactivated EGFR serves as a scaffold for downstream adapters, leading to activation of MAP kinases.

Fig. 3. Novel signal transduction mechanisms mediated by ATj. Ang II phosphorylates multiple tyrosine kinases, such as JAK, FAK, Pyk2, p130Cas, and PI3K. Activated tyrosine kinases phosphorylate many downstream targets including the MAP kinase cascade. Src associates with the adapter protein complex, Shc-GRB2-Sos, that induces guanine nucleotide exchange on the small G protein Ras-GDP/GTP. Activated Ras-GTP interacts with Raf, resulting in phosphorylation of MEK, which in turn, phosphorylates MAP kinases, including ERK1/2, JNK/SAPK, and p38. Rho is also activated through ATi receptors. In addition, Ang II influences activity of receptor tyrosine kinases (RTK), such as EGFR, and PDGFR. The transactivated EGFR serves as a scaffold for downstream adapters, leading to activation of MAP kinases.

and growth. Increased activation of c-Src by Ang II may be an important mediator of cardiac hypertrophy and altered VSMC function in hypertension.

8.2. JAK-STATActivation

Similar to cytokine receptors and RTKs, AT1 activates the JAK/STAT signaling pathway. There are four JAK proteins in mammalian cells: JAK1, JAK2, JAK3, and TYK2

(85). JAKs bind specifically to intracellular domains of cytokine receptor signaling chains and catalyze ligand-induced phosphorylation of themselves and of intracellular tyrosine residues on the receptor, creating tyrosine-phosphorylated docking sites for STATs. Tyrosine phosphorylation of STATs leads to STAT homo- and hetero-dimerization. STAT dimers are rapidly transported from the cytoplasm to the nucleus, where they activate gene transcription. ATi activates JAK2 and Tyk2 in the cardiovascular system

(86). ATi receptor-induced activation of JAKs leads to phosphorylation of the STAT proteins p91/84 (STAT1a/p), p113 (STAT2), and p92 (STAT3). The JAK-STAT signaling pathway activates early growth response genes, providing a mechanism whereby Ang II may influence vascular and cardiac growth, remodeling, and repair (87,88). The STATs have an important role in Ao gene expression in cardiac myocytes. Ang II-induced

Ao gene upregulation, by STAT3 and STAT6 activation, may constitute part of an autocrine, positive-feedback loop that contributes to cardiac hypertrophy in vivo (86).

8.3. FAK and Pyk2 Activation

FAK is a cytoplasmic protein tyrosine kinase localized to regions called focal adhesions. Many stimuli can induce tyrosine phosphorylation and activation of FAK, including integrins and growth factors. The major site of autophosphorylation, tyrosine 397, is a docking site for the SH2 domains of Src family proteins. The other sites of phosphorylation are phosphorylated by Src kinases (89). As a consequence of association with c-Src, FAK undergoes further tyrosine phosphorylation, which results in FAK binding to Grb2, Sos, and Ras. This in turn leads to ERK1/2 activation. Ang II-induced activation of FAK causes its translocation to sites of focal adhesion with the extracellular matrix and phosphorylation of paxillin and talin, which may be involved in the regulation of cell morphology and movement (90). ATj-induced FAK activation also has an important role in Ang II-mediated hypertrophic responses in cardiomyocytes and VSMC (91). The link between the ATj receptor and FAK is unknown, but the Rho family of GTPases may be important.

Another FAK family member, Pyk2, also known as cell adhesion kinase-^, related adhesion focal tyrosine kinase and calcium-dependent tyrosine kinase (the rat homolog of Pyk2), is activated by ATj and is dependent on increased intracellular Ca2+ and PKC (90,92). Because Pyk2 is a candidate to regulate c-Src and to link G protein-coupled vasoconstrictor receptors with protein tyrosine kinase-mediated contractile, migratory and growth responses, it may be a potential point of convergence between Ca2+-dependent signaling pathways and protein tyrosine kinase pathways in cardiovascular cells.

8.4. p130Cas p130Cas is an Ang II-activated tyrosine kinase that plays a role in cytoskeletal rearrangement. This protein serves as an adapter molecule since it contains proline-rich domains, an SH3 domain, and binding motifs for the SH2 domains of Crk and Src. p130Cas is important for integrin-mediated cell adhesion, by the recruitment of cytoskeletal signaling molecules such as FAK, paxillin and tensin to the focal adhesions (93). The phosphorylation of p130Cas is dependent on Ca2+, c-Src, and PKC, and requires an intact cytoskeletal network. Other studies reported that Ang II-induced activation of p130Cas is Ca2+ and PKC independent (94). Although the exact functional significance of Ang II-induced activation of p130Cas is unclear, it might regulate a-actin expression, cellular proliferation, migration, and cell adhesion. p130Cas also has a critical role in cardiovascular development and actin filament assembly.

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