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

Gugasyan, R; Quilici, C; I, STT; Grail, D; Verhagen, AM; Roberts, A; Kitamura, T; Dunn, AR; Lock, P

Author(s): Gugasyan, R; Quilici, C; I, STT; Grail, D; Verhagen, AM; Roberts, A; Kitamura, T; Dunn, AR; Lock, P;
Details: Publication Year 2002-07-08,Volume 158,Issue #1,Page 115-125
Journal Title: JOURNAL OF CELL BIOLOGY
Publication Type: Journal Article
Abstract: Downstream of kinase (Dok)-related protein (DokR, also known as p56(dok)/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 cell. 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.
Publisher: ROCKEFELLER UNIV PRESS
Keywords: CHRONIC MYELOGENOUS LEUKEMIA; ADAPTER PROTEIN; SIGNAL-TRANSDUCTION; TYROSINE PHOSPHORYLATION; THYMOCYTE DEVELOPMENT; PROGENITOR CELLS; PROFOUND BLOCK; MICE LACKING; KINASE PAK1; RECEPTOR
Publisher's Version: https://doi.org/10.1083/jcb.200112066
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2002-07-08 12:00:00