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Review
. 2023 Dec 21;14(12):853.
doi: 10.1038/s41419-023-06380-0.

WWP1 E3 ligase at the crossroads of health and disease

Abhayananda Behera  1 , Aramati Bindu Madhava Reddy  2
Affiliations
Review

WWP1 E3 ligase at the crossroads of health and disease

Abhayananda Behera et al. Cell Death Dis. .

Abstract

The E3 ubiquitin ligase WWP1 (WW Domain-containing E3 Ubiquitin Protein Ligase 1) is a member of the HECT (Homologous to the E6-associated protein Carboxyl Terminus) E3 ligase family. It is conserved across several species and plays crucial roles in various physiological processes, including development, cell growth and proliferation, apoptosis, and differentiation. It exerts its functions through ubiquitination or protein-protein interaction with PPXY-containing proteins. WWP1 plays a role in several human diseases, including cardiac conditions, neurodevelopmental, age-associated osteogenic disorders, infectious diseases, and cancers. In solid tumors, WWP1 plays a dual role as both an oncogene and a tumor suppressor, whereas in hematological malignancies such as AML, it is identified as a dedicated oncogene. Importantly, WWP1 inhibition using small molecule inhibitors such as Indole-3-Carbinol (I3C) and Bortezomib or siRNAs leads to significant suppression of cancer growth and healing of bone fractures, suggesting that WWP1 might serve as a potential therapeutic _target for several diseases. In this review, we discuss the evolutionary perspective, structure, and functions of WWP1 and its multilevel regulation by various regulators. We also examine its emerging roles in cancer progression and its therapeutic potential. Finally, we highlight WWP1's role in normal physiology, contribution to pathological conditions, and therapeutic potential for cancer and other diseases.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. WWP1 is an evolutionarily well-conserved gene.
A. Evolutionary relationships of WWP1 across various species. The amino acid sequence of WWP1 is aligned using the ClustalW algorithm, and the evolutionary history was inferred using the Neighbor joining method. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Dayhoff matrix-based method and are in the units of the number of amino acid substitutions per site. All positions containing alignment gaps and missing data were eliminated only in pairwise sequence comparisons (pairwise deletion option). Phylogenetic analyses were conducted in MEGA11. B The schematic representation of the structure of WWP1 was shown using the InterPro Scan (https://www.ebi.ac.uk/interpro/about/interproscan) and DOG 2.0 (http://dog.biocuckoo.org/) databases. The C2 domain, four WW domain and HECT domain are conserved from lower organisms to higher organisms were shown. C Percentage identity of evolutionarily conserved WWP1 from different species.
Fig. 2
Fig. 2. Activation and autoinhibition of WWP1.
A The cartoon depicts WWP1 E3 ligase transfers ubiquitin (Ub) molecules from E2 to E3, finally from E3 to its _target substrates. Ub binds to catalytically active cysteine site of the E1 activating enzyme in an ATP-dependent manner. The E1 enzyme transfers the ubiquitin molecule to the catalytically active cysteine site of the E2 conjugating enzyme. E2 transfers the Ub molecule to the catalytically active cysteine site of E3 ubiquitin ligating enzyme by interacting with the N-terminus site of the WWP1 HECT domain. Finally, HECT domain transfers the Ub to the _targeting substrate, which interacts with the WW domain of the WWP1. WWP1 directs different polyubiquitination linkages of its substrates: K27 polyubiquitination of PTEN and DVL2, K48 linkage of p27 and KLF5, K63-linked polyubiquitination of EGFR MUC1 etc. However, whether WWP1 directs polyubiquitination of its substrates through other linkages (K6, K11, K29 and K33) remains to be identified (denoted by a red question mark). B Wild-type WWP1 is autoinhibited through intramolecular interaction by sequestering its HECT domain in between the 2,3-linker and WW2-WW3 domains. C Mutations in the HECT domain disrupt the intramolecular autoinhibitory activity of WWP1 leading to its activation. D Intermolecular autoinhibition is carried out by the HECT domain of WWP1 which is sequestered in between the WW2 to WW3 linker domain. E The mutation in both the HECT domain inhibits the dimerization of WWP1.
Fig. 3
Fig. 3. Diverse physiological functions of WWP1.
A LIN-12 regulates the central vulval formation by interacting with DSL ligand. EGFR-RAS-MAPK signaling pathway inhibits LIN-12, whereas WWP1 promotes ubiquitination and degradation of LIN-12 to induce lateral vulva formation in C. elegans. B Suppressor of Deltex (Su(dx)), the Drosophila homolog of WWP1 ubiquitinates and degrades Pez protein to maintain Drosophila midgut homeostasis. C WWP1 regulates granulocyte proliferation in Crassostrea gigas through unknown mechanism. D WWP1 regulates ciliary dynamics in vertebrates by ubiquitinating Ptch1 and recruiting Smo. E Shn3 negatively regulates osteoblast function by recruiting WWP1 for the ubiquitination and degradation of RUNX2. Furthermore, WWP1 inhibits osteoblast differentiation and migration by proteasomal degradation of JUNB and lysosomal degradation of CXCR4. F SOX9 transcriptionally upregulates WWP1/WWP2/miR-140 and miR-140 represses Fyn kinase mRNA expression, which ultimately regulates axon-dendrite polarity. G WWP1 inhibits centra nervous system regeneration and maintains neuromuscular junction integrity by interacting with and regulating Nogo-A via unknown mechanism. H WWP1 maintains cell density by monoubiquitinating AMOTL2, which then interacts with LATS1 and SAV1 to phosphorylate YAP1.
Fig. 4
Fig. 4. Role of WWP1 in various pathological conditions.
A WWP1 plays crucial role in several viral diseases, where it helps in viral budding by interacting with host machineries. For instance, WWP1 interacts with and facilitates polyubiquitination of Ebola virus VP40 (eVP40) matrix proteins. Then, it interacts with and recruits endosomal sorting complexes required for transport III (ESCRT-III) complex to the neck of the viral vesicles, ultimately leading to the release/budding of the EBOLA virus particles. B WWP1 interacts with spastic paraplegia 20 (SPG20)/Spartin to promote its monoubiquitination, subcellular localization, and protein levels, thereby regulating the proper number and size of lipid droplets and ultimately maintaining proper neuronal health. Deregulation of WWP1 alters this pathway, leading to neurological diseases like Troyer syndrome. C WWP1 mutation (arginine to glutamine at 441, R441Q) impairs WWP1-mediated ubiquitination of αENaC (amiloride-sensitive epithelial sodium channel), leading to hypernatremia and chicken muscular dystrophy. D WWP1 regulates aging in C. elegans via two reported mechanisms. First, WWP1 directly interacts with and facilitates multiple monoubiquitination of KLF-1 (kruppel-like factor-1), an essential and specific regulator of dietary restriction (DR)-induced longevity in C. elegans. Second, WWP1 gets phosphorylated by the DAF-2 insulin/IGF-1 signaling pathway (crucial for aging in C. elegans) and therefore might be instrumental for aging. E WWP1 promotes osteogenic diseases such as osteoporosis via ubiquitination and degradation of RUNX2 and JUNB (crucial transcription factors for osteogenic differentiation), which is antagonized by miR-142-5p. F WWP1 promotes cardiac disorders such as left ventricular hypertrophy and lethal ventricular arrhythmias by ubiquitination-mediated degradation of Connexin 43 (Cx43). WWP1 also promotes pressure overload-induced cardiac hypertrophy via promoting K27-mediated polyubiquitination of disheveled segment polarity protein 2 (DVL2) and thereby enhancing the DVL2/CaMKII/HDAC4/MEF2C signaling pathway.
Fig. 5
Fig. 5. Functional implications of WWP1 in cancer.
Schematic representation of the role of WWP1 in cancer. A WWP1 promotes growth and proliferation of cancer cells via different mechanisms. A1 For example, WWP1 promotes polyubiquitination and proteasomal degradation of cell cycle inhibitor p27Kip1 and thereby facilitates cell cycle progression in AML. A2 WWP1 promotes non-degradative K27-lnked polyubiquitination of PTEN, inhibits its dimerization and thereby activates PI3K/AKT signaling to promote cell proliferation in prostate cancer. A3 WWP1 promotes breast cancer cell proliferation by facilitating proteasomal degradation of LATS1. In contrast, WWP1 plays a context-dependent tumor suppressor role in breast cancer by degrading oncogene KLF5, which is counteracted by oncogene YAP/TAZ. B WWP1 inhibits apoptosis in OSCC by enhancing proteasomal degradation of p63α, which is counteracted by PIN1. C WWP1 either promotes or inhibits cancer metastasis. C1 WWP1 promotes CXCL12-mediated CXCR4 lysosomal degradation to inhibit bone metastasis. C2 On the contrary, WWP1 promotes invasion and distant metastasis in CRC and PTC via enhancing the PI3K/AKT signaling. C3 WWP1 also promotes osteosarcoma invasion by increasing the MMPs and β-catenin expression while decreasing that of E-cadherin D TGFβ enhances CK2β activation in a TGFβR-I kinase-dependent manner, and that activated CK2β promotes TGFβ-induced EMT. WWP1 leads to CK2β ubiquitination and proteasomal degradation to inhibit EMT. E WWP1 inhibits resistance to doxorubicin-induced apoptosis in breast cancer by promoting ubiquitination and proteasomal degradation of both ΔNp63 and TAp63. F WWP1 promotes the cancer stemness of NSCLC by promoting ubiquitination and stabilization of EGFR with the help of tribbles pseudokinase 3 (TRIB3).
Fig. 6
Fig. 6. Regulatory mechanisms of WWP1 in cancer.
WWP1 is regulated both at transcriptional and post-transcriptional levels in cancer. A In normal condition, the membrane dimeric form of PTEN inactivates the PI3K and AKT signaling pathway and thereby prevents tumor formation. However, the oncogenic transcription factor MYC transcriptionally upregulates WWP1 levels. WWP1 then promotes non-degradative K27 polyubiquitination of PTEN to inhibit its dimerization, membrane recruitment, and tumor-suppressive functions, leading to tumor initiation and progression. MYC-driven WWP1 upregulation also promotes NDFIP1 ubiquitination and degradation to promote proliferation and metastasis of ICC. B Post-transcriptionally, various tumor suppressor miRNAs such as miR-452, miR-584-5p, and miR-16 bind to 3′UTR of WWP1 mRNA leading to its degradation or translation inhibition and ultimately attenuation of proliferation, invasion, migration of prostate cancer, gastric (GC) and colorectal cancer (CRC). C miR-142 (a tumor suppressor miRNA) binds with the 3’UTR of WWP1 mRNA and degrades it. CircWAC, an oncogenic circular RNA, increases the expression of WWP1 by sponging miR-142 and activate PI3K-AKT signaling pathway and chemotherapy resistance in TNBC. D lncRNA SNHG12 sequesters the tumor suppressor miR-129-5p, upregulates WWP1 expression, and promotes the proliferation and invasion of lung squamous cell carcinoma.
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References

    1. Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, et al. Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J Biol Chem. 1995;270:14733–41. doi: 10.1074/jbc.270.24.14733. - DOI - PubMed
    1. Bork P, Sudol M. The WW domain: a signalling site in dystrophin? Trends Biochem Sci. 1994;19:531–3. doi: 10.1016/0968-0004(94)90053-1. - DOI - PubMed
    1. Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, et al. Identification of novel human WW domain-containing proteins by cloning of ligand _targets. J Biol Chem. 1997;272:14611–6. doi: 10.1074/jbc.272.23.14611. - DOI - PubMed
    1. Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, et al. Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Mol Cell Neurosci. 1998;11:149–60. doi: 10.1006/mcne.1998.0677. - DOI - PubMed
    1. Kasanov J, Pirozzi G, Uveges AJ, Kay BK, Characterizing, Class IWW. domains defines key specificity determinants and generates mutant domains with novel specificities. Chem Biol. 2001;8:231–41. doi: 10.1016/S1074-5521(01)00005-9. - DOI - PubMed

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