Induction of Apoptosis after Expression of PYK2, a Tyrosine Kinase Structurally Related to Focal Adhesion Kinase

Abstract

Many cells (e.g., epithelial cells) require attachment to the extracellular matrix (ECM) to survive, a phenomenon known as anchorage-dependent cell survival. Disruption of the cell–ECM interactions mediated by the integrin receptors results in apoptosis. Focal adhesion kinase (FAK), a 125-kD protein tyrosine kinase activated by integrin engagement, appears to be involved in mediating cell attachment and survival. Proline-rich tyrosine kinase 2 (PYK2), also known as cellular adhesion kinase β (CAKβ) and related adhesion focal tyrosine kinase, is a second member of the FAK subfamily and is activated by an increase in intracellular calcium levels, or treatment with TNFα and UV light. However, the function of PYK2 remains largely unknown. In this study, we show that over-expression of PYK2, but not FAK, in rat and mouse fibroblasts leads to apoptotic cell death. Using a series of deletion mutants and chimeric fusion proteins of PYK2/FAK, we determined that the NH2-terminal domain and tyrosine kinase activity of PYK2 were required for the efficient induction of apoptosis. Furthermore, the apoptosis mediated by PYK2 could be suppressed by over-expressing catalytically active v-Src, c-Src, phosphatidylinositol-3-kinase, or Akt/protein kinase B. In addition, it could also be suppressed by overexpressing an ICE or ICE-like proteinase inhibitor, crmA, but not Bcl2. Collectively, our results suggest that PYK2 and FAK, albeit highly homologous in primary structure, appear to have different functions; FAK is required for cell survival, whereas PYK2 induces apoptosis in fibroblasts.

Cardiomyocyte Apoptosis Triggered by RAFTK/pyk2 via Src Kinase Is Antagonized by Paxillin

“…Caspase activation leads to proteolytic cleavage of anchorage-mediated survival signaling elements such as Akt (58,59), FAK (60, 61), ␤-catenin (62,63), and p130CAS (64) that coordinate cell attachment with cell architecture, movement and gene expression. Induction of apoptosis by RAFTK/ pyk2 is a novel finding for cardiomyocytes that is consistent with previous observations in other cell types (16,65).…”

Dephosphorylation of Focal Adhesion Kinase (FAK) and Loss of Focal Contacts Precede Caspase-mediated Cleavage of FAK during Apoptosis in Renal Epithelial Cells

“…Expression of a constitutively active FAK, a CD2-FAK chimer that localizes to focal adhesions, but not chimers containing FAK kinase-dead mutants, inhibit anoikis (46,51). In contrast to the anti-apoptotic role of FAK, overexpression of proline-rich tyrosine kinase 2, also known as cellular adhesion kinase ␤, a FAK related non-receptor protein tyrosine kinase that also localizes at focal adhesion, induces apoptosis (50). Thus, different FAK family members may have opposing roles in regulating apoptosis.…”

Characterization of the apoptosis-associated tyrosine kinase (AATYK) expressed in the CNS

“…Because overexpression of kinase-inactive AATYK did not interfere with the apoptosis induced by the lowKCl medium, we cannot conclude at this moment that endogenous AATYK works as a proapoptotic factor. However, because proline-rich tyrosine kinase 2 (PYK2), a nonreceptor tyrosine kinase highly expressed in adult brain, has a similar proapoptotic e ect in heterologous cells (Xiong and Parsons, 1997) and multiple myeloma cells (Chauhan et al, 1999), we hypothesize that AATYK serves as a proapoptotic factor in neurons.…”