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About the Authors:
Jeffrey Chiang
* E-mail: [email protected]
Affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
Richard J. Hodes
Affiliations Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
The signal transduction pathways underlying T cell development and activation have been intensively studied. It has been demonstrated that pre-TCR/TCR stimulation results in activation of a signaling cascade initiated by phosphorylation and activation of TCR-ζ, Lck, and ZAP-70, which in turn phosphorylate downstream targets including LAT and SLP-76 [1], [2]. LAT and SLP-76 then activate downstream molecules such as Grb2, GADS, Vav1, ITK and PLC-γ [3], [4]. This cascade represents a widely cited current model of signaling requirements for T cell development. Evidence supporting the requirement for specific elements of this cascade has included biochemical analysis of pre-TCR/TCR signaling as well as compelling data derived from genetic manipulation to knock out or inactivate the genes encoding components of this pathway. Thus, inactivation of individual genes such as those encoding Lck, ZAP-70, LAT, SLP-76, or Vav1 results in severe compromise in thymic T cell development. Of interest, however, our work and that of other laboratories has suggested that the requirements for components of this canonical TCR signaling pathway may not be absolute, and that observed requirements may reflect, at least in part, events that limit the ability of alternative molecular mechanisms to support pre-TCR/TCR-driven T cell development.
Among the molecules that have been demonstrated to have a strong negative regulatory influence on TCR signaling is the Cbl family of proteins [5]. Three members of the Cbl family, c-Cbl (Cbl), Cbl-b and Cbl-3, are expressed in mammalian cells. All Cbl members contain a highly conserved N-terminal region containing a TKB (tyrosine kinase binding) domain and a RING finger domain that has enzymatic E3 ubiquitin ligase activity which mediates inhibition of TCR signal transduction. Only Cbl and Cbl-b have proline-rich region and UBA (ubiquitin associated) domains [5], [6]. Cbl proteins interact with multiple signaling molecules including Lck, Vav, TCR-ζ, PLC- γ1, and Grb2[5], [7]. Cbl has been identified as the most critical member of the Cbl family for...