The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems

Abstract

The tyrosine kinase Pyk2 is vital for integrating receptor-mediated signals controlling adhesion and motility in neuronal, epithelial, and hematopoietic cell types. In T cells, the stimulation of the TCR and costimulatory, chemokine, cytokine, and integrin receptors leads to the phosphorylation of Pyk2 and the induction of its catalytic activity. However, our understanding of the mechanism of the TCR-induced, site-specific phosphorylation of this kinase is incomplete and contradictory. To address this issue, the role of individual signaling pathways in the phosphorylation of Pyk2 tyrosines 402 and 580 upon TCR activation was assessed in human T cells. In contrast to other receptor systems, the TCR-induced phosphorylation of Pyk2 tyrosines 402 and 580 was dependent on the Src family kinases, Fyn or Lck. Interestingly, the TCR-mediated phosphorylation of Pyk2 tyrosines 402 and 580 did not require Ca(2+) influx, ZAP-70 activation, actin cytoskeleton rearrangement, or PI3K function. These observations are different than other receptor systems, which require the induction of one or more of these pathways. Together, these data have defined more fully the mechanism for the TCR-induced phosphorylation of specific sites on Pyk2, suggesting that the TCR has a distinct pathway for the activation of Pyk2 compared with other receptor systems.

Role of Increased Guanosine Triphosphate Cyclohydrolase-1 Expression and Tetrahydrobiopterin Levels upon T Cell Activation

“…In endothelial cells, proline-rich tyrosine kinase 2 (Pyk2) is induced rapidly upon exposure to shear stress in a redox-sensitive fashion (37). Likewise, Pyk2 is induced by T cell receptor ligation and promotes production of TH 2 cytokines in vivo (38,39). The precise roles of these signaling pathways leading to GTPCH-1 activation remain undefined.…”

Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity

“…Activation of Pyk2 typically involves membrane depolarization and calcium influx and is initiated by autophosphorylation at Tyr 402 (1, 4 -7), although additional kinases, including the Tyr receptor kinases EGF receptor and HER2/3, have also been implicated in this process (50,51). Tyr 402 serves as a docking site for the binding of Src and Fyn through their SH2 domains (13,53).…”

Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement

“…Fyn and/or Lck associate with FAK and Pyk2 and control FAK and Pyk2 phosphorylation downstream of the TCR [7–10, 23, 34, 36–38]. In Fyn −/− T cells, anti-CD3 antibody induced phosphorylation of FAK and Pyk2 is reduced [36, 37].…”

“…In Fyn −/− T cells, anti-CD3 antibody induced phosphorylation of FAK and Pyk2 is reduced [36, 37]. Similarly, after treatment with the SFK inhibitor PP2, the TCR-inducible phosphorylation of Pyk2 Y402 and Y580 is dramatically decreased in the human T cell lines and activated primary human T cells [8–10]. Inhibition of Ca 2+ influx, PI3K function, actin cytoskeletal reorganization or ZAP-70 expression does not alter TCR-mediated Pyk2 phosphorylation on Y402 or Y580 [10].…”