ArticleMolecular and cellular biology2009
The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation.
Article in Molecular and cellular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- Role and therapeutic potential of the NEDD4 family in breast cancer.Frontiers in pharmacology · 2025Review
- HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- WWP1 E3 ligase at the crossroads of health and disease.Cell death & disease · 2023Review
- The role of NEDD4 related HECT-type E3 ubiquitin ligases in defective autophagy in cancer cells: molecular mechanisms and therapeutic perspectives.Molecular medicine (Cambridge, Mass.) · 2023Review
- E3 ubiquitin ligases in the acute leukemic signaling pathways.Frontiers in physiology · 2022Review
- The emerging role of WWP1 in cancer development and progression.Cell death discovery · 2021Review
- WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein.Frontiers in cell and developmental biology · 2021Review
- Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system.FASEB bioAdvances · 2020Article
- High expression of WWP1 predicts poor prognosis and associates with tumor progression in human colorectal cancer.American journal of cancer research · 2018Article
- WW-Domain Containing Protein Roles in Breast Tumorigenesis.Frontiers in oncology · 2018Review
- Article
- ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1).PloS one · 2017Article
- The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation.Oncotarget · 2016Article
- Featured Article: Nuclear export of opioid growth factor receptor is CRM1 dependent.Experimental biology and medicine (Maywood, N.J.) · 2016Article
- NEDD4 single nucleotide polymorphism rs2271289 is associated with keloids in Chinese Han population.American journal of translational research · 2016Article
- Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer.The Journal of biological chemistry · 2015Article
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- WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
- Knockdown of WWP1 inhibits growth and invasion, but induces apoptosis of osteosarcoma cells.International journal of clinical and experimental pathology · 2015Article
- Regulation of ERBB3/HER3 signaling in cancer.Oncotarget · 2014Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
In general, epidermal growth factor receptor family members stimulate cell proliferation. In contrast, at least one HER4 isoform, JM-a/Cyt1, inhibits cell growth after undergoing a two-step proteolytic cleavage that first produces a membrane-anchored 80-kDa fragment (m80(HER4)) and subsequently liberates a soluble 80-kDa fragment, s80(HER4). Here we report that s80(HER4) Cyt1 action increased the expression of WWP1 (for WW domain-containing protein 1), an E3 ubiquitin ligase, but not other members of the Nedd4 E3 ligase family. The HER4 Cyt1 isoform contains three proline-rich tyrosine (PY) WW binding motifs, while Cyt2 has only two. WWP1 binds to all three Cyt1 PY motifs; the interaction with PY2 found exclusively in Cyt1 was strongest. WWP1 ubiquitinated and caused the degradation of HER4 but not of EGFR, HER2, or HER3. The HER4-WWP1 interaction also accelerated WWP1 degradation. Membrane HER4 (full length and m80(HER4), the product of the first proteolytic cleavage) were the preferred targets of WWP1, correlating with the membrane localization of WWP1. Conversely s80(HER4), a poorer WWP1 substrate, was found in the cell nucleus, while WWP1 was not. Deletion of the C2 membrane association domain of WWP1 allowed more efficient s80(HER4) degradation, suggesting that WWP1 is normally part of a membrane complex that regulates HER4 membrane species levels, with a predilection for the growth-inhibitory Cyt1 isoform. Finally, WWP1 expression diminished HER4 biologic activity in MCF-7 cells. We previously showed that nuclear s80(HER4) is ubiquitinated and degraded by the anaphase-promoting complex, suggesting that HER4 ubiquitination within specific cellular compartments helps regulate the unique HER4 signaling capabilities.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.