CD2BP3, CIN85 and the structurally related adaptor protein CMS bind to the same CD2 cytoplasmic segment, but elicit divergent functional activities.
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 p130(Cas) 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.
Tibaldi
Elena V
EV
Laboratory of Immunobiology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Reinherz
Ellis L
EL
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D018801:CD2 Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D013601:T-Lymphocytes / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; C493841:BCAR1 protein, human; D018801:CD2 Antigens; C114545:CD2-associated protein; D002352:Carrier Proteins; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; C433810:SH3KBP1 protein, human