![]() ![]() In addition, c-Cbl is constitutively phosphorylated in LMP2A-expressing LCLs ( Engels et al., 2001). ![]() These interactions suggest that c-Cbl may interact with LMP2A-associated proteins with functional consequences. Cbl proteins preferentially interact with and target Src-family PTKs including Lyn, Fyn and Lck for degradation ( Andoniou et al., 2000 Kaabeche et al., 2004 Rao et al., 2002 Sanjay et al., 2001). Syk is a target of Cbl-mediated ubiquitination and degradation upon BCR stimulation ( Rao et al., 2001). Two Nedd4-family E3s, Nedd4 and AIP4/Itch, bind to three Cbl-family proteins and target them for degradation, which inhibits Cbl-mediated desensitization of activated EGFR and non-receptor c-Src PTKs ( Courbard et al., 2002 Magnifico et al., 2003). Several previous studies have shown that c-Cbl interacts with known LMP2A-associated proteins. The phosphorylation of Cbl proteins following signal stimulation is essential for the pivotal role of Cbl proteins for their adaptor function ( Swaminathan and Tsygankov, 2006). ![]() Cbl proteins are multivalent adapter proteins capable of interacting with multiple signal components ( Swaminathan and Tsygankov, 2006). These targets include Src-family and Syk PTKs ( Swaminathan and Tsygankov, 2006). c-Cbl is a RING-finger E3 that negatively regulates the BCR and other signal pathways by targeting multiple signal molecules for degradation. The proto-oncogenic protein c-Cbl and other Cbl-family proteins have been recognized as key players in the negative regulation of antigen receptor and other signaling pathways ( Swaminathan and Tsygankov, 2006). The phosphorylation of B cell signal molecules is critical for their recruitment to the plasma membrane and the formation of BCR signalosome. LMP2A ubiquitin-dependent processes are likely important for LMP2A function in EBV latent infection such as the modulation of LMP2A-induced signals which alter normal B cell development ( Casola et al., 2004 Ikeda et al., 2004).īCR stimulation triggers the activation of PTKs, which leads to the phosphorylation of numerous signal molecules such as adapter, docking and effecter proteins ( Kurosaki, 2002). In addition, LMP2A ubiquitination negatively regulates LMP2A signal transduction in B cell development ( Ikeda et al., 2003 Ikeda et al., 2004). In contrast to the BCR, LMP2A contains two PY motifs (PPXY) that specifically associate with Nedd4-family ubiquitin-protein ligases (E3s) resulting in the downmodulation of LMP2A activity by ubiquitinating both LMP2A and LMP2A-associated PTKs ( Ikeda et al., 2000 Ikeda et al., 2001 Winberg et al., 2000). The LMP2A amino-terminal domain interacts and activates with the Src family protein tyrosine kinase (PTK) Lyn and the Syk PTK ( Fruehling and Longnecker, 1997 Fruehling et al., 1998 Rovedo and Longnecker, 2008) in a constitutive manner mimicking a BCR providing development and survival signals in the absence of corresponding antigens ( Caldwell et al., 1998). The elucidation of differences between the BCR and LMP2A signaling may aide the development of novel therapeutic agents to treat EBV latent infections and EBV-associated cancers. The understanding of the molecular basis of LMP2A-mediated signaling is essential to clarify the involvement of LMP2A in EBV latent infections and EBV-related malignancies. LMP2A functions as a signalosome by constitutively associating and activating proteins normally associated with the B cell receptor (BCR) ( Longnecker, 2000). Latent membrane protein 2A (LMP2A) is an Epstein-Barr virus (EBV) encoded protein that has been implicated in regulating viral latency and pathogenesis in EBV infections ( Ikeda et al., 2005 Longnecker, 2000).
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |