Different levels of regulation of CXCR4 function on hematopoietic cells. First, expression of CXCR4 is regulated at the transcriptional level by several factors (eg, hypoxia). Second, CXCR4 as well as its ligand SDF-1 are subject to proteolytic degradation by several proteases that are expressed in the hematopoietic microenvironment and serum. Third, CXCR4 after interaction with SDF-1 is internalized from the surface and is recirculated from the endosomal compartment at different rates. Fourth, functionality of the CXCR4 receptor depends on its incorporation into membrane lipid rafts, and several signals from other membrane receptors or integrins may increase the incorporation of CXCR4 into membrane lipid rafts, increasing its signaling.⁴ Finally, as demonstrated by Berthebaud et al, CXCR4 is the subject of negative regulation by RGS16. It is possible that this mechanism plays a role in heterologous desensitization or negative cross-talk of CXCR4 after stimulation of MKs by other chemokines (eg, macrophage inflammatory protein 1β [MIP-1β] or interleukin-8 [IL-8]).