Alternative titles; symbols
HGNC Approved Gene Symbol: WWP2
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38) : 16:69,762,332-69,941,739 (from NCBI)
WWP2 is an E3 ubiquitin ligase that promotes PTEN (601728) degradation (Li et al., 2018).
The WW domain is a 35- to 40-amino acid protein-protein interaction motif characterized by 4 conserved aromatic residues, 2 of which are tryptophan. Using COLT (cloning of ligand targets), Pirozzi et al. (1997) screened human bone marrow and brain cDNA expression libraries with putative WW domain peptide ligand sequences and recovered 3 distinct proteins, WWP1 (602307), WWP2, and WWP3 (602625). WWP2 contains 4 tandem WW domains, a complete HECT (homologous to the E6-associated protein carboxyl terminus) domain, which is associated with ubiquitin-protein ligase activity, and a C2 (calcium-dependent phospholipid-binding)-like domain characteristic of a large family of proteins that includes protein kinase C (see 176960). Based on similarities in structure between NEDD4 (602278) and WWP2, Pirozzi et al. (1997) suggested that WWP2 belongs to a family of NEDD4-like proteins.
By Northern blot analysis, Wood et al. (1998) detected a 5-kb WWP2 transcript in heart, brain, placenta, lung, liver, muscle, kidney, and pancreas.
Xu et al. (2004) cloned mouse Wwp2. The deduced 870-amino acid protein has a calculated molecular mass of 98.7 kD and shares 96% identity with human WWP2. Northern blot analysis detected 2 Wwp2 transcripts, with highest expression in testis, followed by spleen, kidney, and liver. Low expression was detected in brain, heart, and lung, and no expression was detected in skeletal muscle. Immunofluorescence microscopy localized Wwp2 in the nucleus and cytoplasm of mouse embryonic stem cells.
By radiation hybrid analysis, Wood et al. (1998) mapped the WWP2 gene to chromosome 16q21.
Using in vitro assays, Pirozzi et al. (1997) showed that individual WW domains of WWP1, WWP2, and WWP3 could selectively bind particular peptide ligands.
Using yeast 2-hybrid and in vitro binding studies, Wood et al. (1998) demonstrated that WWP2, which they called AIP2, bound to atrophin-1 (DRPLA; 607462).
Using affinity chromatography, Xu et al. (2004) showed that mouse Wwp2 interacted with Oct4 (POU5F1; 164177), a transcription factor that regulates the fate of embryonic stem cells. Mutation analysis showed that the WW domains of Wwp2 were required for the interaction, and both the N- and C-terminal regions of Oct4 could interact with Wwp2. Wwp2 ubiquitinated Oct4 in vitro and in vivo, and this activity required the catalytic cysteine within the HECT domain of Wwp2. Ubiquitination of Oct4 inhibited its transcriptional activity and directed its degradation by the proteasome. Expression of both Wwp2 and Oct4 was reduced with differentiation in mouse embryonic stem cells.
Li et al. (2018) found that the Wwp2-knockout mice were viable but showed reduced body size, weight, and organ size, as well as developmental retardation, compared with wildtype mice. The smaller body phenotype of Wwp2-knockout mice occurred early in development and continued to adulthood. The phenotype of Wwp2-knockout mice resembled that of Pten-transgenic mice. Wwp2 deficiency was found to elevate Pten protein levels in vivo and antagonized PI3K-Akt (164730) signaling. Depletion of Chip (STUB1; 607207), another E3 ubiquitin ligases for Pten, resulted in embryonic lethality but did not affect Pten protein levels and only slightly promoted Akt phosphorylation, indicating that Chip does not ubiquitylate Pten or control its activity. Analysis of Chip/Wwp2 double-knockout mice revealed elevated Pten levels similar to those in Wwp2-knockout mice, demonstrating that Chip and Wwp2 do not have a synergistic effect on Pten degradation and that Wwp2, rather than Chip, is the ubiquitin ligase that promotes Pten degradation in vivo.
Li, H., Zhang, P., Zhang, Q., Li, C., Zou, W., Chang, Z., Cui, C.-P., Zhang, L. WWP2 is a physiological ubiquitin ligase for phosphatase and tensin homolog (PTEN) in mice. J. Biol. Chem. 293: 8886-8899, 2018. [PubMed: 29685889] [Full Text: https://doi.org/10.1074/jbc.RA117.001060]
Pirozzi, G., McConnell, S. J., Uveges, A. J., Carter, J. M., Sparks, A. B., Kay, B. K., Fowlkes, D. M. Identification of novel human WW domain-containing proteins by cloning of ligand targets. J. Biol. Chem. 272: 14611-14616, 1997. [PubMed: 9169421] [Full Text: https://doi.org/10.1074/jbc.272.23.14611]
Wood, J. D., Yuan, J., Margolis, R. L., Colomer, V., Duan, K., Kushi, J., Kaminsky, Z., Kleiderlein, J. J., Jr., Sharp, A. H., Ross, C. A. Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Molec. Cell. Neurosci. 11: 149-160, 1998. [PubMed: 9647693] [Full Text: https://doi.org/10.1006/mcne.1998.0677]
Xu, H. M., Liao, B., Zhang, Q. J., Wang, B. B., Li, H., Zhong, X. M., Sheng, H. Z., Zhao, Y. X., Zhao, Y. M., Jin, Y. Wwp2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination. J. Biol. Chem. 279: 23495-23503, 2004. [PubMed: 15047715] [Full Text: https://doi.org/10.1074/jbc.M400516200]