Dysregulated FcepsilonRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells.
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.
Hernandez-Hansen
Valerie
V
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.
Smith
Alexander J
AJ
Surviladze
Zurab
Z
Chigaev
Alexandre
A
Mazel
Tomas
T
Kalesnikoff
Janet
J
Lowell
Clifford A
CA
Krystal
Gerald
G
Sklar
Larry A
LA
Wilson
Bridget S
BS
Oliver
Janet M
JM
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*
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