title: Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extracellular signal-regulated protein kinase by the stromal cell-derived factor-1 alpha/CXCL12 chemokine.
abstract: Stimulation of T lymphocytes with the ligand for the CXCR4 chemokine receptor stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12), results in prolonged activation of the extracellular signal-regulated kinases (ERK) ERK1 and ERK2. Because SDF-1alpha is unique among several chemokines in its ability to stimulate prolonged ERK activation, this pathway is thought to mediate special functions of SDF-1alpha that are not shared with other chemokines. However, the molecular mechanisms of this response are poorly understood. In this study we show that SDF-1alpha stimulation of prolonged ERK activation in Jurkat T cells requires both the ZAP-70 tyrosine kinase and the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) scaffold protein. This pathway involves ZAP-70-dependent tyrosine phosphorylation of SLP-76 at one or more of its tyrosines, 113, 128, and 145. Because TCR activates ERK via SLP-76-mediated activation of the linker of activated T cells (LAT) scaffold protein, we examined the role of LAT in SDF-1alpha-mediated ERK activation. However, neither the SLP-76 proline-rich domain that links to GADS and LAT, nor LAT, itself are required for SDF-1alpha to stimulate SLP-76 tyrosine phosphorylation or to activate ERK. Together, our results describe the distinct mechanism by which SDF-1alpha stimulates prolonged ERK activation in T cells and indicate that this pathway is specific for cells expressing both ZAP-70 and SLP-76.
authors.affiliation: Department of Surgery, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Kremer
authors.forename: Troy D
authors.initials: TD
authors.lastname: Humphreys
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Nan-Xin
authors.initials: NX
authors.lastname: Qian
authors.forename: Karen E
authors.initials: KE
authors.lastname: Hedin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013379:Substrate Specificity / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C515255:CXCL12 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C409587:GRAP2 protein, human; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D020928:Mitogen-Activated Protein Kinases