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Published online 1 July 2002. doi:10.1083/jcb.200112066
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© The Rockefeller University Press, 0021-9525/2002/7/115 $5.00
The Journal of Cell Biology, Volume 158, Number 1, July 8, 2002 115-125

Article

 Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites

Raffi Gugasyan1, Cathy Quilici2, Stacey T.T. I2,3,4, Dianne Grail2, Anne M. Verhagen1, Andrew Roberts1, Toshio Kitamura5, Ashley R. Dunn2,3 and Peter Lock2,3,4

1 Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville 3050, Australia
2 Ludwig Institute for Cancer Research, University of Melbourne, Parkville 3050, Australia
3 Cooperative Research Centre for Cellular Growth Factors, University of Melbourne, Parkville 3050, Australia
4 Department of Surgery, University of Melbourne, Parkville 3050, Australia
5 The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Address correspondence to Peter Lock, Department of Surgery, University of Melbourne, Level 5 Clinical Sciences Building, Royal Melbourne Hospital, VIC 3050, Australia. Tel.: 61-38-344-5493. Fax: 61-39-347-6488. E-mail: petelock{at}unimelb.edu.au

Downstream of kinase (Dok)–related protein (DokR, also known as p56dok/FRIP/Dok-R) is implicated in cytokine and immunoreceptor signaling in myeloid and T cells. Tyrosine phosphorylation induces DokR to bind the signal relay molecules, RasGTPase-activating protein (RasGAP) and Nck. Here, we have examined the function of DokR during hematopoietic development and the requirement for RasGAP and Nck binding sites in its biological function. Retroviral-mediated expression of DokR in bone marrow cells dramatically inhibited their capacity to form colonies in vitro in response to the cytokines macrophage colony–stimulating factor and stem cell factor, whereas responses to interleukin-3 and granulocyte macrophage colony–stimulating factor were only weakly affected. When introduced into lethally irradiated mice, hematopoietic cells expressing DokR showed a drastically reduced capacity to repopulate lymphoid tissues. Most notably, DokR dramatically reduced repopulation of the thymus, in part by reducing the number of T cell precursors seeding in the thymus, but equally, through inhibiting the transition of CD4-CD8- to CD4+CD8+ T cells. Consequently, the number of mature peripheral T cells was markedly reduced. In contrast, a minimal effect on B cell and myeloid lineage development was observed. Importantly, functional RasGAP and Nck binding sites were found to be essential for the biological effects of DokR in vitro and in vivo.

Key Words: signal transduction; growth inhibition; hematopoiesis; thymocyte; progenitor cell


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