WWP1

Official Full Name

WW domain containing E3 ubiquitin protein ligase 1

Organism

Homo sapiens

GeneID

11059

Background

WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 4 tandem WW domains and a HECT (homologous to the E6-associated protein carboxyl terminus) domain. The encoded protein belongs to a family of NEDD4-like proteins, which are E3 ubiquitin-ligase molecules and regulate key trafficking decisions, including targeting of proteins to proteosomes or lysosomes. Alternative splicing of this gene generates at least 6 transcript variants; however, the full length nature of these transcripts has not been defined. [provided by RefSeq, Jul 2008]

Synonyms

AIP5; Tiul1; hSDRP1;

Bio Chemical Class

mRNA target

Protein Sequence

MATASPRSDTSNNHSGRLQLQVTVSSAKLKRKKNWFGTAIYTEVVVDGEITKTAKSSSSSNPKWDEQLTVNVTPQTTLEFQVWSHRTLKADALLGKATIDLKQALLIHNRKLERVKEQLKLSLENKNGIAQTGELTVVLDGLVIEQENITNCSSSPTIEIQENGDALHENGEPSARTTARLAVEGTNGIDNHVPTSTLVQNSCCSYVVNGDNTPSSPSQVAARPKNTPAPKPLASEPADDTVNGESSSFAPTDNASVTGTPVVSEENALSPNCTSTTVEDPPVQEILTSSENNECIPSTSAELESEARSILEPDTSNSRSSSAFEAAKSRQPDGCMDPVRQQSGNANTETLPSGWEQRKDPHGRTYYVDHNTRTTTWERPQPLPPGWERRVDDRRRVYYVDHNTRTTTWQRPTMESVRNFEQWQSQRNQLQGAMQQFNQRYLYSASMLAAENDPYGPLPPGWEKRVDSTDRVYFVNHNTKTTQWEDPRTQGLQNEEPLPEGWEIRYTREGVRYFVDHNTRTTTFKDPRNGKSSVTKGGPQIAYERGFRWKLAHFRYLCQSNALPSHVKINVSRQTLFEDSFQQIMALKPYDLRRRLYVIFRGEEGLDYGGLAREWFFLLSHEVLNPMYCLFEYAGKNNYCLQINPASTINPDHLSYFCFIGRFIAMALFHGKFIDTGFSLPFYKRMLSKKLTIKDLESIDTEFYNSLIWIRDNNIEECGLEMYFSVDMEILGKVTSHDLKLGGSNILVTEENKDEYIGLMTEWRFSRGVQEQTKAFLDGFNEVVPLQWLQYFDEKELEVMLCGMQEVDLADWQRNTVYRHYTRNSKQIIWFWQFVKETDNEVRMRLLQFVTGTCRLPLGGFAELMGSNGPQKFCIEKVGKDTWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE

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Detailed Information

WWP1 (WW Domain Containing E3 Ubiquitin Protein Ligase 1) encodes a HECT-type E3 ubiquitin ligase and belongs to the NEDD4-like protein family. The protein structure includes four tandem WW domains, which mediate protein–protein interactions, and a C-terminal HECT domain responsible for ubiquitin transfer. WWP1 recognizes specific substrates and catalyzes the transfer of ubiquitin from E2 conjugating enzymes to target proteins, thereby regulating their stability, localization, or function. In the TGF-β signaling pathway, WWP1 interacts with the inhibitory Smad7 and promotes ubiquitination and degradation of the TGF-β type I receptor (TGFBR1), providing negative feedback to limit TGF-β–mediated cell differentiation and apoptosis. Unlike other E3 ligases such as Smurf1/2, WWP1 does not directly ubiquitinate R-Smads like Smad2; instead, it indirectly inhibits Smad2 phosphorylation through receptor degradation, highlighting its pathway specificity. WWP1 also participates in Hippo pathway regulation: under conditions of cell contact inhibition, it is recruited to the Crumbs complex at the cell membrane, monoubiquitinates AMOTL2, and activates LATS2 kinase. Activated LATS2 phosphorylates the transcription coactivator YAP1, causing its cytoplasmic retention and loss of transcriptional activity, ultimately suppressing cell proliferation.

Figure 1. The chemical constitution of WWP1. (Hu X, et al., 2021)

Physiological and Pathological Roles

The diversity of WWP1 substrates underlies its dual roles in physiology and pathology. In tissue homeostasis and development, WWP1 regulates endothelial cell function by promoting the degradation of transcription factors KLF2 and KLF5. It also mediates ubiquitination and degradation of the tumor suppressor TP63 (p63), influencing epithelial development and stem cell maintenance. In cancer, WWP1 exhibits context-dependent effects. It is overexpressed in multiple tumor types. For example, in prostate cancer, WWP1 ubiquitinates the tumor suppressor PTEN, promoting its nuclear export and functional inactivation, which accelerates tumor progression. Conversely, in breast cancer, WWP1 can degrade the oncogenic receptor ERBB4 (JM-A CYT-1 isoform), thereby inhibiting tumor growth, illustrating tissue-specific functionality. Beyond cancer, WWP1 mutations are associated with autosomal recessive hereditary spastic paraplegia (SPG20), where loss of WWP1 disrupts neuronal protein homeostasis. WWP1 also modulates immune signaling by ubiquitinating molecules such as RNF11, which regulates NF-κB activity without inducing degradation, affecting chronic inflammatory responses.

Figure 2. Activation and autoinhibition of WWP1. (Behera A, et al., 2023)

Translational Potential

Targeting WWP1 has been explored through small-molecule inhibitors and gene silencing approaches. Preclinical studies using compounds that inhibit the HECT domain of WWP1 have demonstrated reduced cancer cell proliferation and enhanced chemotherapy sensitivity, although the broad range of WWP1 substrates raises concerns about potential toxicity in normal tissues. WWP1 expression may serve as a biomarker for pathway activity and therapeutic resistance, and its interplay with the Hippo pathway suggests opportunities for combination therapy with YAP1-targeted drugs. Moreover, WWP1's role in immune regulation provides a potential avenue for modulating the tumor-immune microenvironment. Overall, WWP1 functions as a central hub in ubiquitination networks, offering potential intervention points in cancer and neurodegenerative diseases. Future strategies should integrate conditional knockout models and substrate-specific inhibitors to optimize therapeutic efficacy while minimizing adverse effects.

Despite being at an early stage of translational research, WWP1's function as a ubiquitination network hub provides a potential target for therapeutic intervention, warranting further studies to balance efficacy and safety.

Reference

Behera A, Reddy ABM. WWP1 E3 ligase at the crossroads of health and disease. Cell Death Dis. 2023 Dec 21;14(12):853.
Hu X, Yu J, Lin Z, et al. The emerging role of WWP1 in cancer development and progression. Cell Death Discov. 2021 Jun 21;7(1):163.

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