'Reverse gear' cellular movement mediated by chemokines.
We sought to model the mechanism by which leucocytes may be actively repulsed by a beta-chemokine signal. This model is used to interpret an apparent paradox in chemokine biology, whereby high levels of a T-cell chemoattractant, stromal cell derived factor-1 (SDF-1), are present in bone marrow and thymic tissues despite a paucity of mature T lymphocytes in these areas. We postulate the differential involvement in cell migration of the two binding sites on SDF-1 for its sole receptor, CXCR4, depending on whether high or low concentrations of SDF-1 are encountered by the cell. Site choice would be mediated by divergent affinities of the two binding interactions. We also propose differential signalling following SDF-1/CXCR4 interactions on the plasma membrane versus ligand/receptor complexes in endocytic vesicles. Preliminary data showing divergent susceptibility to kinase inhibitors depending on whether a cell is attracted to or repulsed by SDF-1, are consistent with this model. In terms of physical movement toward or away from a chemokine gradient, we compare the cycling of surface receptors during migration to the caterpillar drive of a tractor, which can change direction simply by altering the direction of rotation of its threads. Finally, the potential clinical implications of concentration-dependent, chemokine-based cell attraction and repulsion are discussed.
Zlatopolskiy
A
A
Laboratory for AIDS Virus Research, Weill Medical College, Cornell University, New York, New York 10021, USA. jlaurenc@mail.med.cornell.edu
Laurence
J
J
D000818:Animals; D001665:Binding Sites; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D019281:Dimerization; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4