International Immunology, Vol. 15, No. 3, pp. 313-329,
March 2003
© 2003 Japanese Society for Immunology
CD2BP3, CIN85 and the structurally related adaptor protein CMS bind to the same CD2 cytoplasmic segment, but elicit divergent functional activities
1 Laboratory of Immunobiology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Correspondence to: E. L. Reinherz; E-mail: ellis_reinherz{at}dfci.harvard.edu
Transmitting editor: S. Koyasu
Interaction trap cloning was used to identify a CD2 cytoplasmic tail-binding protein termed CD2BP3. CD2BP3 is the major RNA splice variant of the CIN85 locus in human T lymphocytes, lacking SH3A, the first of three SH3 domains found in CIN85, but retaining SH3B, SH3C, a proline-rich domain and C-terminal coiled coil. CD2BP3 has 35% amino acid identity to CMS, a structurally related protein binding to the same highly conserved segment of the CD2 tail and known to be involved in T cell polarization/cytoskeletal interactions. Unlike CMS, however, CD2BP3 does not co-localize with F-actin and binds p130Cas weakly, if at all. Moreover, CIN85/CD2BP3 proteins are readily degraded by TCR cross-linking, consistent with the presence of a PEST sequence C-terminal to SH3C. CIN85 SH3A and CIN85/CD2BP3 SH3B bind to proline-rich segments within CIN85/CD2BP3 themselves as evidenced by mAb accessibility analysis and protein interaction studies including c-Cbl binding. This form of intramolecular regulation is not manifest by CMS. CMS and CIN85 activities are antagonistic, while the functions of CIN85 and CD2BP3 are also distinct. Thus, CD2-mediated adhesion, signaling and cell motility are regulated in a highly complex manner.
Keywords: c-Cbl, cytoskeletal polarization, intramolecular regulation, RNA splicing, T cell
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