title: Regulation of FcRγ function by site-specific serine phosphorylation.
abstract: The common FcRγ, an immunoreceptor tyrosine-based activation motif (ITAM)- containing adaptor protein, associates with multiple leukocyte receptor complexes and mediates signal transduction through the ITAM in the cytoplasmic domain. The presence of multiple serine and threonine residues within this motif suggests the potential for serine/threonine phosphorylation in modulating signaling events. Single-site mutational analysis of these residues in RBL-2H3 cells indicates that each may contribute to net FcRγ-mediated signaling, and mass spectrometry of WT human FcRγ from receptor-stimulated cells shows consistent preferential phosphorylation of the serine residue at position 51. Immunoblot analysis, mass spectrometry, and mutational analyses showed that phosphorylation of serine 51 in the 7-residue spacer between the 2 YxxL sequences regulates FcRγ signaling by inhibiting tyrosine phosphorylation at the membrane proximal Y47 position of the ITAM, but not phosphorylation at position Y58. This inhibition results in reduced Syk recruitment and activation. With in vitro kinase assays, PKC-δ and PKA show preferential phosphorylation of S51. Serine/threonine phosphorylation of the FcRγ ITAM, which functions as an integrator of multiple signaling elements, may explain in part the contribution of variants in PKC-δ and other PKC isoforms to some autoimmune phenotypes.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Spandan
authors.initials: S
authors.lastname: Shah
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and agibson@uabmc.edu.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Gibson
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Chuanyi
authors.initials: C
authors.lastname: Ji
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Darrington
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: James
authors.initials: J
authors.lastname: Mobley
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
mesh_terms: D020816:Amino Acid Motifs; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
chemical_list: C000622314:FCER1G, human; D011961:Receptors, Fc; D010768:Phosphoserine; D013912:Threonine; D000072377:Syk Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C
keywords: ITAM; Syk recruitment; adaptor protein; receptor inhibition; signaling protein