WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a 
rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine 
receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from 
patients with WHIM syndrome display impaired CXCR4 internalization and enhanced 
chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely 
contribute to the clinical manifestations. Here, we investigated the biochemical 
mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after 
ligand activation, WHIM-associated mutant CXCR4 receptors lacking the 
carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than 
wild-type (WT) receptors, while utilizing the same trafficking endocytic 
pathway. Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active 
WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, 
while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its 
trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant 
receptor whereas Grk3 associates normally. Since beta-Arrestins and Grks play 
critical roles in phosphorylation and internalization of agonist-activated G 
protein-coupled receptors, these results provide a molecular basis for CXCR4 
dysfunction in WHIM syndrome.