title: Dysregulated FcepsilonRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells.
abstract: Studies in B cells from Lyn-deficient mice have identified Lyn as both a kinetic accelerator and negative regulator of signaling through the BCR. The signaling properties of bone marrow-derived mast cells from Lyn(-/-) mice (Lyn(-/-) BMMCs) have also been explored, but their signaling phenotype remains controversial. We confirm that Lyn(-/-) BMMCs release more beta-hexosaminidase than wild-type BMMCs following FcepsilonRI cross-linking and show that multiple mast cell responses to FcepsilonRI cross-linking (the phosphorylation of receptor subunits and other proteins, the activation of phospholipase Cgamma isoforms, the mobilization of Ca(2+), the synthesis of phosphatidylinositol 3,4,5-trisphosphate, the activation of the alpha(4)beta(1) integrin, VLA-4) are slow to initiate in Lyn(-/-) BMMCs, but persist far longer than in wild-type cells. Mechanistic studies revealed increased basal as well as stimulated phosphorylation of the Src kinase, Fyn, in Lyn(-/-) BMMCs. Conversely, there was very little basal or stimulated tyrosine phosphorylation or activity of the inositol phosphatase, SHIP, in Lyn(-/-) BMMCs. We speculate that Fyn may substitute (inefficiently) for Lyn in signal initiation in Lyn(-/-) BMMCs. The loss of SHIP phosphorylation and activity very likely contributes to the increased levels of phosphatidylinositol 3,4,5-trisphosphate and the excess FcepsilonRI signaling in Lyn(-/-) BMMCs. The unexpected absence of the transient receptor potential channel, Trpc4, from Lyn(-/-) BMMCs may additionally contribute to their altered signaling properties.
authors.affiliation: Department of Pathology and Cancer Research and Treatment Center, University of New Mexico School of Medicine, CRF 205, 2325 Camino De Salud, Albuquerque, NM 87131, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Hernandez-Hansen
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Zurab
authors.initials: Z
authors.lastname: Surviladze
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chigaev
authors.forename: Tomas
authors.initials: T
authors.lastname: Mazel
authors.forename: Janet
authors.initials: J
authors.lastname: Kalesnikoff
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilson
authors.forename: Janet M
authors.initials: JM
authors.lastname: Oliver
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D039041:Integrin alpha4beta1 / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D017455:Receptors, IgE / Q000502:physiology*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D010738:Type C Phospholipases / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D039041:Integrin alpha4beta1; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017455:Receptors, IgE; D019089:Stem Cell Factor; D014443:Tyrosine; D015759:Ionomycin; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium