Abnormal chemokine-induced responses of immature and mature hematopoietic cells from motheaten mice implicate the protein tyrosine phosphatase SHP-1 in chemokine responses

Chemokines regulate a number of biological processes, including trafficking of diverse leukocytes and proliferation of myeloid progenitor cells. SHP-1 (Src homology 2 domain tyrosine phosphatase 1), a phosphotyrosine phosphat ase, is considered an important regulator of signaling for a number of cyto kine receptors. Since specific tyrosine phosphorylation of proteins is impo rtant for biological activities induced by chemokines, we examined the role of SHP-1 in functions of chemokines using viable motheaten (me(v)/me(v)) m ice that were deficient in SHP-1. Chemotactic responses to stromal call-der ived factor 1 (SDF-1), a CXC chemokine, were enhanced. with bone marrow mye loid progenitor cells as well as macrophages, T cells, and B cells from me( v)/me(v) versus wild-type (+/+) mice. SDF-1-dependent actin polymerization and activation of mitogen-activated protein kinases were also greater in me (v)/me(v) versus +/+ cells. In contrast, immature subsets of me(v)/me(v) bo ne marrow myeloid progenitors were resistant to effects of a number of chem okines that suppressed proliferation of +/+ progenitors. These altered chem okine responses did not appear to be due to enhanced expression of CXCR-4 o r lack of chemokine receptor expression. However, expression of some chemok ine receptors (CCR1, CCR2, CCR3, and CXCR2) was significantly enhanced in m e(v)/me(v) T cells. Our results implicate SHP-1 involvement in a number of different chemokine-induced biological activities.