title: SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis.
abstract: The chemokine CXCL12 induces prolonged focal adhesion kinase (FAK) phosphorylation and sustained proadhesive responses in progenitor bone-marrow (BM) B cells, but not in mature peripheral B cells. Here we demonstrate that suppressor of cytokine signaling 3 (SOCS3) regulated CXCL12-induced FAK phosphorylation through the ubiquitin-proteasome pathway. CXCL12 triggered increased FAK ubiquitination in mature B cells, but not in progenitor B cells. Accordingly, SOCS3 expression was low in progenitor B cells, increased in immature B cells, and highest in mature B cells. SOCS3 overexpression in pro-B cells impaired CXCL12-induced FAK phosphorylation and proadhesive responses. Conversely, SOCS3-deficient mature B cells from Cre(MMTV)Socs3(fl/fl) mice exhibited prolonged FAK phosphorylation and adhesion to VCAM-1. In contrast to wild-type mice, Cre(MMTV)Socs3(fl/fl) mice had a 2-fold increase in immature B cells, which were evenly distributed in endosteal and perisinusoidal BM compartments. We propose that the developmental regulation of CXCR4-FAK signaling by SOCS3 is an important mechanism to control the lodgement of B cell precursors in the BM microenvironment.
authors.affiliation: Children's Hospital Boston and Joint Program in Transfusion Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Le
authors.forename: Bing-Mei
authors.initials: BM
authors.lastname: Zhu
authors.forename: Brendan
authors.initials: B
authors.lastname: Harley
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: John P
authors.initials: JP
authors.lastname: Manis
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D014162:Transfection; D054875:Ubiquitination; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019010:Vascular Cell Adhesion Molecule-1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse