Mast cells play an important role in many inflammatory and immunological reactions by releasing an array of mediators. The goal of our studies is to understand the intracellular signal transduction pathways that lead to the release of these molecules. In previous studies we observed that protein tyrosine phosphorylation is an early and critical signal for FceRI induced degranulation. The protein tyrosine kinase Syk was found to be tyrosine phosphorylated and activated after receptor aggregation. Syk was also shown to be essential for the receptor-induced release of inflammatory mediators. In recent studies the SH2 domain-mediated membrane translocation was found to be critical for this immune receptor mediated activation of Syk for downstream signaling events and the localization of Syk in glycosphingolipid-enriched microdomains by itself was not enough to generate or enhance signaling events. Studies on the structural basis of the activation of Syk demonstrated that the two adjacent tyrosines in the activation loop were required for downstream signaling. The kinase activity of Syk played the major role in phosphorylating these tyrosines both in vivo and in vitro. Studies with a variant of the rat basophilic leukemia cell line demonstrated that activation of the Cdc42 and/or Rac1 GTPase plays an essential role in immune receptor mediated early signaling that leads to calcium mobilization and degranulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Intramural Research (Z01)
Project #
1Z01DE000696-03
Application #
6507215
Study Section
(OIIB)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Dental & Craniofacial Research
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Oliver, Constance; Fujimura, Akira; Silveira E Souza, Adriana Maria Mariano et al. (2007) Mast cell-specific gangliosides and FcepsilonRI follow the same endocytic pathway from lipid rafts in RBL-2H3 cells. J Histochem Cytochem 55:315-25
Ganguly, Surajit; Grodzki, Cristina; Sugden, David et al. (2007) Neural adrenergic/cyclic AMP regulation of the immunoglobulin E receptor alpha-subunit expression in the mammalian pinealocyte: a neuroendocrine/immune response link? J Biol Chem 282:32758-64
Zhang, Juan; Suzuki, Katsuhiro; Hitomi, Tomohiro et al. (2007) TOM1L1 is a Lyn substrate involved in FcepsilonRI signaling in mast cells. J Biol Chem 282:37669-77
Song, Haifeng; Zhang, Juan; Chiang, Y Jeffrey et al. (2007) Redundancy in B cell developmental pathways: c-Cbl inactivation rescues early B cell development through a B cell linker protein-independent pathway. J Immunol 178:926-35
Zudaire, Enrique; Martinez, Alfredo; Garayoa, Mercedes et al. (2006) Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis. Am J Pathol 168:280-91
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Suzuki-Inoue, Katsue; Wilde, Jonathan I; Andrews, Robert K et al. (2004) Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylation of tyrosine kinase Syk and phospholipase Cgamma2 at distinct sites. Biochem J 378:1023-9
Hitomi, Tomohiro; Zhang, Juan; Nicoletti, Liliana M et al. (2004) Phospholipase D1 regulates high-affinity IgE receptor-induced mast cell degranulation. Blood 104:4122-8
Zhang, Juan; Chiang, Yungping J; Hodes, Richard J et al. (2004) Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor. J Immunol 173:1811-8

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