The protein PTEN is a phosphatase and tumor suppressor whose activity is often decreased in human cancers. Thus, reactivating such a protein could potentially be an effective therapy against cancer. Lee et al. (Science 2019) identified HERC, a ubiquitin E3 ligase (WWP1) as a PTEN-interacting protein that modifies PTEN and inhibits its tumor suppressive activity (see the Perspective by Parsons). Depletion of WWP1 increased dimerization and membrane recruitment of PTEN. A natural compound found to be a pharmacological inhibitor of WWP1 inhibited tumor growth in a mouse model of prostate cancer. Thus, reactivation of the tumor suppressor PTEN may provide a strategy for battling tumors.///////////////Juvenile development fertility 2
Three radiation-induced alleles of the mouse p locus, p6H, p25H, and pbs, cause defects in growth, coordination, fertility,
and maternal behavior in addition to p gene-related hypopigmentation. These alleles are associated with disruption of
the p gene plus an adjacent gene involved in the disorders listed. The adjacent gene, previously
named rjs (runty jerky sterile), was identified by positional cloning. Lehman et al. 1998; The rjs cDNA is very large, covering 15,264 nucleotides. The
predicted rjs-encoded protein (4,836 amino acids) contains several sequence motifs, including three RCC1 repeats, a
structural motif in common with cytochrome b5, and a HECT domain in common with E6-AP ubiquitin ligase.The fertility problems associated with p6H, p25H, and pbs mutations include spermatocyte and oocyte
abnormalities and possible endocrinological deficits. Males homozygous for p6H, p25H, or pbs are sterile and
exhibit testicular hypoplasia, abnormal spermatogenesis, and abnormal sperm morphology manifested as multinucleated
and multitailed sperm with acrosome abnormalities and disorganized mitochondria spirals. Ovaries from mice
homozygous for p6H, p25H, and pbs contain large numbers of developing follicles, but few, if any, corpora lutea or
corpora hemorrhagica Meldvold et al .
NCBI Summary:
This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]
General function
Intracellular signaling cascade, Apoptosis
Comment
Based on the conserved motifs, mouse
mutation studies, and by analogy to the related HERC1, it has been suggested that human HERC2 may act as a guanine nucleotide exchange factor and E3 ubiquitin ligase, with function in protein trafficking and degradation pathways in the cell (Ji et al. 1999) . The mouse Herc2 gene has been cloned, mutations of which were shown to cause severe developmental delay, jerky gait, sterility, and juvenile lethality in a recessively inherited manner (jdf2, or rjs) (Lehman et al. 1998;)(Ji et al. 1999) .
Cellular localization
Cytoplasmic, Mitochondrial
Comment
Ovarian function
Comment
Expression regulated by
Comment
Ovarian localization
Comment
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Mutations of the mouse pink-eyed dilution locus, p, are defined by hypopigmentation, ranging from a
minor diminution in coat color (with dark eyes) to a nearly complete lack of melanin pigment (with
pink eyes). The radiation-induced p alleles p6H, p25H, and pbs are associated with additional
phenotypes including reduced growth, jerky gait, male sterility, female semisterility, and maternal
behavior defects. The locus associated with these phenotypes has been named rjs (runty
jerky sterile) Lyon et al and jdf2 (juvenile development and fertility) Rinchik et al .