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School of Surgery and Pathology, University of Western Australia, Crawley, Western Australia, Australia
c-Cbl and Cbl-b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules. By comparing bone marrow-derived mast cells from c-Cbl and Cbl-b-deficient mice it has recently been shown that Cbl-b is the dominant family member for negatively regulating signaling responses from high-affinity IgE receptors. In this study, we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl-b-deficient mice is the relatively higher levels of Cbl-b protein over c-Cbl in mast cells compared with other hemopoietic cells. We also directly compare mast cells from c-Cbl and Cbl-b-deficient mice and find that loss of Cbl-b, but not c-Cbl, increases cell growth, retards receptor internalization, and causes the sustained tyrosine phosphorylation of Syk and its substrates. However, loss of Cbl-b does not enhance the activation of ERK or Akt, nor does it promote a greater calcium response. Furthermore, loss of Cbl-b or c-Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases. Most notable, however, is the extremely large increase in the production of proinflammatory cytokines TNF-
, IL-6, and MCP-1 by Cbl-b–/– mast cells compared with levels produced by c-Cbl–/– or wild-type cells. This marked induction, which appears to be restricted to these three cytokines, is dependent on IgE receptor activation and correlates with enhanced I
B kinase phosphorylation. Thus, Cbl-b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Health and Medical Research Council (Canberra) and the Medical and Health Research Infrastructure Fund (Western Australian State Government).
2 Current address: Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria 3052, Australia.
3 Address correspondence and reprint requests to Dr. Wallace Y. Langdon, School of Surgery and Pathology, University of Western Australia, Crawley, Western Australia 6009, Australia. E-mail address: wlangdon{at}cyllene.uwa.edu.au
4 Abbreviations used in this paper: PTK, protein tyrosine kinase; SH2, Src homology 2; LAT, linker for activation of T cells; LAB, linker for activation of B cells; SLP-76, SH2-containing leukocyte protein of 76 kDa; PLC, phospholipase C; Gab, Grb2-associated-binder; BMMC, bone marrow-derived cultured mast cell; wt, wild type; IKK, IB kinase.
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