Chemokine signaling specificity: essential role for the N-terminal domain of chemokine receptors

Biochemistry. 2007 Aug 7;46(31):8961-8. doi: 10.1021/bi7004043. Epub 2007 Jul 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • COS Cells
  • Chemokine CXCL1
  • Chemokine CXCL6
  • Chemokines, CXC / metabolism
  • Chlorocebus aethiops
  • Endocytosis / drug effects
  • Endocytosis / physiology
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism*
  • Interleukin-8 / pharmacology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Molecular
  • Mutant Chimeric Proteins / metabolism
  • Phosphorylation / drug effects
  • Rabbits
  • Receptors, Interleukin-8 / genetics
  • Receptors, Interleukin-8 / metabolism*
  • Receptors, Interleukin-8A / genetics
  • Receptors, Interleukin-8A / metabolism
  • Receptors, Interleukin-8B / genetics
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transfection

Substances

  • CXCL1 protein, human
  • CXCL6 protein, human
  • Chemokine CXCL1
  • Chemokine CXCL6
  • Chemokines, CXC
  • Interleukin-8
  • Mutant Chimeric Proteins
  • Receptors, Interleukin-8
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3