The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including regulated and targeted proteasomal degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). UBE2L3 is a member of the E2 conjugating enzyme family and cloning of the human gene was first described by Moynihan et al. (1996). Human UBE2L3 has been mapped to chromosome 22q11.2-q13.1 and shares 97% homology with its mouse homologue (Moynihan et al., 1996; Moynihan et al., 1998). UBE2L3 efficiently mediates the ubiquitylation of E6AP (Nuber et al., 1996). A protein complex comprising UBE2L3, the E3 ligase Parkin and alpha synuclein (alpha-Sp22) has been identified in which the substrate alpha-Sp22 becomes polyubiquitylated in normal human brains and targeted for degradation. Loss of Parkin function causes pathologic accumulation of alpha-Sp22 in the brain which is associated with Parkinson's disease (Shimura et al., 2001). UBE2L3 acts with E6-associated protein (E6-AP) to synergistically enhance the transcriptional activity of the progesterone receptor (PR) and increase its interaction with the steroid receptor coactivator 1 (SRC-1) (Verma et al., 2004). Binding of UBE2L3 to the amino-terminal domain (NTD) of SMAD 7 stimulates E3 ligase Smurf activity via its HECT domain; recruitment of the complex to the TGFbeta receptor facilitates receptor degradation during TGFbeta signalling (Ogunjimi et al., 2005). Changes in levels of UBE2L3 during the cell cycle regulate entrance into and progression through S phase. UBE2L3 levels decrease during S-phase but are restored in G2, it is thought progression into G2 occurs by UBE2L3 modulation of the intra-S phase checkpoint mediated by Chk1 (Whitcomb et al., 2009).
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