Chemokine signaling specificity: essential role for the N-terminal domain of chemokine receptors |
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Authors: | Prado Gregory N Suetomi Katsutoshi Shumate David Maxwell Carrie Ravindran Aishwarya Rajarathnam Krishna Navarro Javier |
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Institution: | Department of Neuroscience and Cell Biology, Sealy Centers for Molecular Medicine and Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555, USA. |
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Abstract: | Chemokine IL-8 (CXCL8) binds to its cognate receptors CXCR1 and CXCR2 to induce inflammatory responses, wound healing, tumorogenesis, and neuronal survival. Here we identify the N-loop residues in IL-8 (H18 and F21) and the receptor N-termini as the major structural determinants regulating the rate of receptor internalization, which in turn controlled the activation profile of ERK1/2, a central component of the receptor/ERK signaling pathway that dictates signal specificity. Our data further support the idea that the chemokine receptor core acts as a plastic scaffold. Thus, the diversity and intensity of inflammatory and noninflammatory responses mediated by chemokine receptors appear to be primarily determined by the initial interaction between the receptor N-terminus and the N-loop of chemokines. |
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