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

Oncogene volume 18, pages 6733–6740 (1999)Cite this article

Abstract

Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a member of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNFα, UV light and increases in intracellular calcium levels. However, the function of RAFTK remains largely unknown. Our previous studies demonstrated that treatment with dexamethasone (Dex), ionizing radiation (IR), and anti-Fas mAb induces apoptosis in multiple myeloma (MM) cells. In the present study, we examined the potential role of RAFTK during induction of apoptosis 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 with 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 overexpression 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 apoptosis. Finally, interleukin-6 (IL-6), a known survival factor for MM cells, 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 cells.

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Acknowledgements

We thank Dr Hawa Avraham for anti-RAFTK Ab; for GFP-RAFTK, RAFTK K457M (K-M), RAFTK Y402F, and RAFTK wild type (WT) constructs; and for critical reading of the manuscript. Drs Erica Golemis and Arnold Freedman kindly provided the GST-HEF constructs. This investigation was supported by PHS grants CA50947 (K Anderson) and CA75216 (S Kharbanda) awarded by the National Cancer Institute, a Kathy Giusti Multiple Myeloma Research Foundation Fellowship (D Chauhan), and DHHS grant HL55445 (S Avraham). Hervé Husson is supported by the Association pour la Recherche sur le Cancer (ARC).

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Authors and Affiliations

  1. Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Dharminder Chauhan, Teru Hideshima, Pramod Pandey, Steve Treon, Gerrard Teoh, Noopur Raje, Hervé Husson, Surender Kharbanda & Kenneth C Anderson

  2. Division of Experimental Medicine and Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, 02115, Massachusetts, MA, USA

    Shalom Avraham

  3. Northwestern University Medical School, Robert H Lurie Cancer Center, Chicago, 60611, Illinois, IL, USA

    Steven Rosen & Nancy Krett

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  1. Dharminder Chauhan
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Chauhan, D., Hideshima, T., Pandey, P. et al. RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. Oncogene 18, 6733–6740 (1999). https://doi.org/10.1038/sj.onc.1203082

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