Basophil FcɛRI histamine release parallels expression of Src-homology 2–containing inositol phosphatases in chronic idiopathic urticaria

2007 ◽  
Vol 119 (2) ◽  
pp. 441-448 ◽  
Author(s):  
Becky M. Vonakis ◽  
Kavitha Vasagar ◽  
Scott P. Gibbons ◽  
Laura Gober ◽  
Patricia M. Sterba ◽  
...  
Keyword(s):  
Histamine Release ◽  
Chronic Idiopathic Urticaria ◽  
Src Homology 2 ◽  
Src Homology ◽  
Inositol Phosphatases

scholarly journals Two Distinct Tyrosine-based Motifs Enable the Inhibitory Receptor FcγRIIB to Cooperatively Recruit the Inositol Phosphatases SHIP1/2 and the Adapters Grb2/Grap

2004 ◽  
Vol 279 (50) ◽  
pp. 51931-51938 ◽  
Author(s):  
Isabelle Isnardi ◽  
Renaud Lesourne ◽  
Pierre Bruhns ◽  
Wolf H. Fridman ◽  
John C. Cambier ◽  
...  
Keyword(s):  
Cell Activation ◽  
Sh2 Domain ◽  
Scaffold Proteins ◽  
Src Homology 2 ◽  
Dependent Cell ◽  
Trimolecular Complex ◽  
Src Homology ◽  
Inositol Phosphatases ◽  
Necessary And Sufficient ◽  
Activation Motif

FcγRIIB are low-affinity receptors for IgG that contain an immunoreceptor tyrosine-based inhibition motif (ITIM) and inhibit immunoreceptor tyrosine-based activation motif (ITAM)-dependent cell activation. When coaggregated with ITAM-bearing receptors, FcγRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5′-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcγRIIB ITIM was proposed to be necessary and sufficient for recruiting SHIP1/2. We show here that a second tyrosine-containing motif in the intracytoplasmic domain of FcγRIIB is required for SHIP1/2 to be coprecipitated with the receptor. This motif functions as a docking site for the SH2 domain-containing adapters Grb2 and Grap. These adapters interact via their C-terminal SH3 domain with SHIP1/2 to form a stable receptor-phosphatase-adapter trimolecular complex. Both Grb2 and Grap are required for an optimal coprecipitation of SHIP with FcγRIIB, but one adapter is sufficient for the phosphatase to coprecipitate in a detectable manner with the receptors. In addition to facilitating the recruitment of SHIPs, the second tyrosine-based motif may confer upon FcγRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.

scholarly journals IL-6 blocks a discrete early step in lymphopoiesis

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 879-885 ◽  
Author(s):  
Kazuhiko Maeda ◽  
Yoshihiro Baba ◽  
Yoshinori Nagai ◽  
Kozo Miyazaki ◽  
Alexander Malykhin ◽  
...  
Keyword(s):  
Target Cells ◽  
Hematopoietic Progenitors ◽  
Early Step ◽  
Hematopoietic Stem ◽  
Lymphoid Lineage ◽  
Src Homology 2 ◽  
Multipotent Progenitors ◽  
Src Homology ◽  
Src Homology 2 Domain

Abstract Animals lacking Src homology 2 domain-containing inositol 5-phosphatase (SHIP) display a reduction in lymphopoiesis and a corresponding enhancement of myelopoiesis. These effects are mediated at least in part by elevated levels of interleukin 6 (IL-6). Here, we show the lymphopoiesis block in SHIP–/– mice is due to suppression of the lymphoid lineage choice by uncommitted progenitors. The suppression can be reproduced in vitro with recombinant IL-6, and IL-6 acts directly on hematopoietic progenitors. The block is partially overcome in SHIP–/– IL-6–/– double-deficient animals. IL-6 does not suppress but actually enhances proliferation of lymphoid-committed progenitors, indicating the IL-6 target cells are hematopoietic stem cells or multipotent progenitors. The findings suggest a mechanism for the lymphopenia that accompanies proinflammatory diseases.

scholarly journals PLC-γ directly binds activated c-Src, which is necessary for carbachol-mediated inhibition of NHE3 activity in Caco-2/BBe cells

2013 ◽  
Vol 305 (3) ◽  
pp. C266-C275 ◽  
Author(s):  
Nicholas C. Zachos ◽  
Luke J. Lee ◽  
Olga Kovbasnjuk ◽  
Xuhang Li ◽  
Mark Donowitz
Keyword(s):  
Sh2 Domain ◽  
Signaling Proteins ◽  
Multiprotein Complexes ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Inhibitor ◽  
Intracellular Ca ◽  
Direct Binding ◽  
Src Homology

Elevated levels of intracellular Ca2+([Ca2+]i) inhibit Na+/H+exchanger 3 (NHE3) activity in the intact intestine. We previously demonstrated that PLC-γ directly binds NHE3, an interaction that is necessary for [Ca2+]iinhibition of NHE3 activity, and that PLC-γ Src homology 2 (SH2) domains may scaffold Ca2+signaling proteins necessary for regulation of NHE3 activity. [Ca2+]iregulation of NHE3 activity is also c-Src dependent; however, the mechanism by which c-Src is involved is undetermined. We hypothesized that the SH2 domains of PLC-γ might link c-Src to NHE3-containing complexes to mediate [Ca2+]iinhibition of NHE3 activity. In Caco-2/BBe cells, carbachol (CCh) decreased NHE3 activity by ∼40%, an effect abolished with the c-Src inhibitor PP2. CCh treatment increased the amount of active c-Src as early as 1 min through increased Y416phosphorylation. Coimmunoprecipitation demonstrated that c-Src associated with PLC-γ, but not NHE3, under basal conditions, an interaction that increased rapidly after CCh treatment and occurred before the dissociation of PLC-γ and NHE3 that occurred 10 min after CCh treatment. Finally, direct binding to c-Src only occurred through the PLC-γ SH2 domains, an interaction that was prevented by blocking the PLC-γ SH2 domain. This study demonstrated that c-Src 1) activity is necessary for [Ca2+]iinhibition of NHE3 activity, 2) activation occurs rapidly (∼1 min) after CCh treatment, 3) directly binds PLC-γ SH2 domains and associates dynamically with PLC-γ under elevated [Ca2+]iconditions, and 4) does not directly bind NHE3. Under elevated [Ca2+]iconditions, PLC-γ scaffolds c-Src into NHE3-containing multiprotein complexes before dissociation of PLC-γ from NHE3 and subsequent endocytosis of NHE3.

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