The Chemokine Monocyte Chemotactic Protein 1 Triggers Janus Kinase 2 Activation and Tyrosine Phosphorylation of the CCR2B Receptor

• Published in: The Journal of immunology (1950) Vol. 161; no. 2; pp. 805 - 813
• Main Authors: Mellado, M, Rodriguez-Frade, J. M, Aragay, A, del Real, G, Martin, A. M, Vila-Coro, A. J, Serrano, A, Mayor, F., Jr, Martinez-A., C
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.07.1998
• Subjects: Amino Acid Substitution - genetics; Calcium - metabolism; Cell Line; Chemokine CCL2 - pharmacology; Enzyme Activation - drug effects; Humans; Janus Kinase 2; Phosphorylation; Protein-Tyrosine Kinases - drug effects; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins; Receptors, CCR2; Receptors, Chemokine - drug effects; Receptors, Chemokine - metabolism; Receptors, Chemokine - physiology; Receptors, Cytokine - drug effects; Receptors, Cytokine - metabolism; Receptors, Cytokine - physiology; Signal Transduction - drug effects; Tyrosine - genetics; Tyrosine - metabolism; Virulence Factors, Bordetella - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.161.2.805

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.