title: Negative regulation of chemokine receptor signaling and B-cell chemotaxis by p66Shc.
abstract: Shc (Src homology 2 domain containing) adaptors are ubiquitous components of the signaling pathways triggered by tyrosine kinase-coupled receptors. In lymphocytes, similar to other cell types, the p52 and p66 isoforms of ShcA/Shc participate in a self-limiting loop where p52Shc acts as a positive regulator of antigen receptor signaling by promoting Ras activation, whereas p66Shc limits this activity by competitively inhibiting p52Shc. Based on the fact that many signaling mediators are shared by antigen and chemokine receptors, including p52Shc, we have assessed the potential implication of p66Shc in the regulation of B-cell responses to chemokines, focusing on the homing receptors CXCR4 (C-X-C chemokine receptor type 4) and CXCR5 (C-X-C chemokine receptor type 5). The results identify p66Shc as a negative regulator of the chemotactic responses triggered by these receptors, including adhesion, polarization and migration. We also provide evidence that this function is dependent on the ability of p66Shc to interact with the chemokine receptors and promote the assembly of an inhibitory complex, which includes the phosphatases SHP-1 (Src homology phosphatase-1) and SHIP-1 (SH2 domain-containing inositol 5'-phosphatase-1), that results in impaired Vav-dependent reorganization of the actin cytoskeleton. This function maps to the phosphorylatable tyrosine residues in the collagen homology 1 (CH1) domain. The results identify p66Shc as a negative regulator of B-cell chemotaxis and suggest a role for this adaptor in the control of B-cell homing.
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Patrussi
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Capitani
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cannizzaro
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Finetti
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: O M
authors.initials: OM
authors.lastname: Lucherini
authors.affiliation: Department of Molecular Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: C T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D054380:Receptors, CXCR5 / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; C513179:CXCR5 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D058539:Phosphatidylinositol 3-Kinase; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases