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*
Department of Immunology and Oncology, Centro Nacional de Biotecnología, and
Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científica (CSIC)-Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain
The chemokines are a growing family of low m.w., 70- to 80-residue proinflammatory cytokines that operate by interacting with G protein-coupled receptors. Chemokines are involved in cell migration and in the activation of specific leukocyte subsets. Using the Mono Mac 1 monocytic cell line, we show that monocyte chemotactic protein 1 (MCP-1) triggers activation of the Janus kinase 2 (JAK2)/STAT3 pathway and CCR2 receptor tyrosine phosphorylation. Both Ca2+ mobilization and cell migration are blocked in Mono Mac 1 cells by tyrphostin B42, a specific JAK2 kinase inhibitor. Within seconds of MCP-1 activation, JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor. This MCP-1-initiated phosphorylation and association to JAK2 is also observed in CCR2B-transfected HEK293 cells. In contrast, when a CCR2B Tyr139Phe mutant is expressed in HEK293 cells, it is not phosphorylated in tyrosine and triggers neither JAK2/STAT3 activation nor Ca2+ mobilization in response to MCP-1. These results implicate the tyrosine kinase pathway in early chemokine signaling, suggesting a key role for this kinase in later events.
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V. Lukashova, C. Asselin, J. J. Krolewski, M. Rola-Pleszczynski, and J. Stankova G-protein-independent Activation of Tyk2 by the Platelet-activating Factor Receptor J. Biol. Chem., June 22, 2001; 276(26): 24113 - 24121. [Abstract] [Full Text] [PDF]
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M. Roque, W. J.H. Kim, M. Gazdoin, A. Malik, E. D. Reis, J. T. Fallon, J. J. Badimon, I. F. Charo, and M. B. Taubman CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 554 - 559. [Abstract] [Full Text] [PDF]
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