The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasome-dependent 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). Cas-Br-M Murine Ecotropic Retroviral Transforming Sequence Homolog (CBL) is a member of the E3 protein ligase family and cloning of the human gene was first described by Langdon et al. (1989). A single c-CBL locus termed CBL2 has been mapped to human chromosome 11q23. This region of chromosome 11 is involved in translocations and deletions in a broad range of leukaemias; c-CBL has been found to be translocated from chromosome 11 in leukaemias with either t(4;11) or t(11;14) abnormalities (Savage et al.,1991; Wei et al., 1990). Ubiquitylation of receptor protein-tyrosine kinases (rPTKs) terminates signalling by marking active receptors for degradation. CBL is an adaptor protein for rPTKs. Recent studies have shown that CBL is a positive regulator of rPTK ubiquitylation by activating E2 enzymes through its RING finger domain and targeting substrates such as the Platelet Derived Growth Factor Receptor (PDGFR) through its SH2 domain (Joazeiro et al., 1999). Ubiquitylation of the Hepatocyte Growth Factor (HGF) receptor by CBL has been shown to recruit the endophilin-CIN85 complex resulting in receptor internalisation and degradation (Petrelli, Gilestro et al. 2002). Mutations in a highly conserved alpha helical structure of CBL linking the SH2 and RING finger domains renders CBL proteins oncogenic (Thien et al., 2001). C-CBL(-/-) haematopoietic stem/progenitor cells (HSPCs) have shown enhanced sensitivity to a variety of cytokines compared to C-CBL(+/+) HSPCs. Furthermore, homozygous C-CBL mutations have been found in most 11q-aUPD-positive myeloid malignancies (Sanada et al., 2009).
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