RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells

Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a me mber of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNF a lpha, UV light and increases in intracellular calcium levels. However, the function of RAFTK remains largely unknown. Our previous studies demonstrate d that treatment with dexamethasone (Dex), ionizing radiation (IR), and ant i-Fas mAb induces apoptosis in multiple myeloma (MM) cells. In the present study, we examined the potential role of RAFTK during induction of apoptosi s in human MM cells triggered by these three stimuli. Dex-induced apoptosis , in contrast to apoptosis triggered by anti-Fas mAb or IR, is associated w ith activation of RAFTK. Transient overexpression of RAFTK wild type (RAFTK WT) induces apoptosis, whereas transient overexpression of Kinase inactive RAFTK (RAFTK K-M) blocks Dex-induced apoptosis. In contrast, transient ove rexpression of RAFTK K-M has no effect on apoptosis triggered by IR or Fas. In Dex-resistant cells, Dex does not trigger either RAFTK activation or ap optosis. Finally, interleukin-6 (IL-6), a known survival factor for MM cell s, inhibits both activation of RAFTK and apoptosis of MM.1S cells triggered by Dex. Our studies therefore demonstrate Dex-induced RAFTK-dependent, and IR or Fas induced RAFTK-independent apoptotic signaling cascades in MM cel ls.