Negative regulation of mast cell signaling and function by the adaptor LAB/NTAL.
Engagement of the Fcepsilon receptor I (FcepsilonRI) on mast cells and basophils initiates signaling pathways leading to degranulation. Early activation events include tyrosine phosphorylation of two transmembrane adaptor proteins, linker for activation of T cells (LAT) and non-T cell activation linker (NTAL; also called LAB; a product of Wbscr5 gene). Previous studies showed that the secretory response was partially inhibited in bone marrow-derived mast cells (BMMCs) from LAT-deficient mice. To clarify the role of NTAL in mast cell degranulation, we compared FcepsilonRI-mediated signaling events in BMMCs from NTAL-deficient and wild-type mice. Although NTAL is structurally similar to LAT, antigen-mediated degranulation responses were unexpectedly increased in NTAL-deficient mast cells. The earliest event affected was enhanced tyrosine phosphorylation of LAT in antigen-activated cells. This was accompanied by enhanced tyrosine phosphorylation and enzymatic activity of phospholipase C gamma1 and phospholipase C gamma2, resulting in elevated levels of inositol 1,4,5-trisphosphate and free intracellular Ca2+. NTAL-deficient BMMCs also exhibited an enhanced activity of phosphatidylinositol 3-OH kinase and Src homology 2 domain-containing protein tyrosine phosphatase-2. Although both LAT and NTAL are considered to be localized in membrane rafts, immunogold electron microscopy on isolated membrane sheets demonstrated their independent clustering. The combined data show that NTAL is functionally and topographically different from LAT.
Volná
Petra
P
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic.
Lebduska
Pavel
P
Dráberová
Lubica
L
Símová
Sárka
S
Heneberg
Petr
P
Boubelík
Michael
M
Bugajev
Viktor
V
Malissen
Bernard
B
Wilson
Bridget S
BS
Horejsí
Václav
V
Malissen
Marie
M
Dráber
Petr
P
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D008407:Mast Cells / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D011506:Proteins / Q000502:physiology*; D017455:Receptors, IgE / Q000502:physiology; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002118:Calcium; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D011506:Proteins; D017455:Receptors, IgE; D010738:Type C Phospholipases; D014443:Tyrosine; C471359:LAB protein, mouse; C488163:LAT2 protein, mouse; C491734:Lat protein, mouse