| The HECT domain-containing ubiquitin E3 ligase HECTH9 (also known as HUWE1, ARF-BP1, URE-B1, Mule, and LASU1) is critical for the ubiquitination and proteasomal degradation of many target proteins, and is involved in the regulation of a variety of cellular processes, including DNA replication and base excision repair, cellular proliferation, differentiation, and apoptosis. HECTH9 contains two Armadillo (ARM) repeat-like domains (ARLD1 and ARLD2), a ubiquitin-associated (UBA) domain, a WWE domain, a well-conserved BH3 domain, and a catalytic HECT domain that facilitates ubiquitination of target proteins. HECTH9 has been shown to polyubiquitinate p53, Miz1, N-Myc, Mcl-1, Cdc 6, and DNA polymerase beta through K48-mediated linkage, thereby targeting these proteins for proteosomal degradation. The tumor suppressor protein ARF (known as p14 ARF in humans and p19 ARF in mice) binds to and inhibits the uibiquitin ligase activity toward p53, resulting in stabilization of p53 and induction of apoptosis. HECTH9 has also been shown to polyubiquitinate c-Myc through K63-linkage, which is required for recruitment of p300, activation of c-Myc target genes, and induction of cellular proliferation. HECTH9 is overexpressed in colon, lung, and breast cancer. In addition, defects in HECTH9 result in mental retardation syndromic X-linked Turner type (MRXST) and mental retardation X-linked type 17 (MRX17) syndromes. |
