Beta-chemokine receptor CCR5 signals via the novel tyrosine kinase RAFTK.
Chemokine receptors are coupled to G-proteins and their activation results in prominent changes in cell migration and growth. The downstream signaling pathways that mediate these effects of chemokines are largely uncharacterized. Macrophage inflammatory protein 1 beta (MIP 1 beta) binding to its cognate receptor CCR5 resulted in activation of the related adhesion focal tyrosine kinase (RAFTK), with subsequent activation of the cytoskeletal protein paxillin and the down-stream transcriptional activators, c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 mitogen-activated protein (MAP) kinase. Inhibition of RAFTK by a dominant-negative kinase mutant markedly attenuated JNK/ SAPK activity. Thus, RAFTK appears to provide a functional "bridge" for the transmission of CCR5 receptor signaling to the cytoskeleton and nucleus, primary sites of chemotaxis and growth regulation.
Ganju
R K
RK
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Dutt
P
P
Wu
L
L
Newman
W
W
Avraham
H
H
Avraham
S
S
Groopman
J E
JE
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D054407:Chemokine CCL4; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2; D006801:Humans; D007163:Immunosorbent Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D008223:Lymphoma; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D054407:Chemokine CCL4; D003598:Cytoskeletal Proteins; D019402:Macrophage Inflammatory Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; D019713:Receptors, CCR5; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases