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Chemokine Signaling Specificity:  Essential Role for the N-Terminal Domain of Chemokine Receptors

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journal contribution
posted on 07.08.2007, 00:00 by Gregory N. Prado, Katsutoshi Suetomi, David Shumate, Carrie Maxwell, Aishwarya Ravindran, Krishna Rajarathnam, Javier Navarro
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.