Human Kruppel-like Factor 5 Is a Target of the E3 Ubiquitin Ligase WWP1 for Proteolysis in Epithelial Cells*

The transcription factor KLF5 plays an important role in human carcinogenesis. In epithelial cells, the KLF5 protein is tightly regulated by the ubiquitin-proteasome pathway. To better understand the mechanisms for the regulation of KLF5 protein, we identified and characterized an E3 ubiquitin ligase for KLF5, i.e. WWP1. We found that WWP1 formed a protein complex with KLF5 in vivo and in vitro. Furthermore, WWP1 mediated the ubiquitination and degradation of KLF5, and the catalytic cysteine residue of WWP1 is essential for its function. A PY motif in a transactivation domain of KLF5 is necessary for its interaction with WWP1. Finally, WWP1 was amplified and overexpressed in some cancer cell lines from the prostate and breast, which negatively regulated the function of KLF5 in gene regulation. These findings not only established WWP1 as an E3 ubiquitin ligase for KLF5, they also further implicated the KLF5 pathway in human carcinogenesis.

• Publication year

  2005

• Venue

  Journal of Biological Chemistry

• Publication date

  2005-12-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M506183200PMID 16223724
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Degradation of the Tumor Suppressor Smad4 by WW and HECT Domain Ubiquitin Ligases*

  2005cited by this paper
• Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation.

  2005cited by this paper
• Ubiquitin–proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells

  2005cited by this paper
• Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis

  2005cited by this paper
• The Deacetylase HDAC1 Negatively Regulates the Cardiovascular Transcription Factor Krüppel-like Factor 5 through Direct Interaction*

  2005cited by this paper
• Regulation of Platelet-derived Growth Factor-A Chain by Krüppel-like Factor 5*

  2004cited by this paper
• WWP1-dependent ubiquitination and degradation of the lung Krüppel-like factor, KLF2.

  2004cited by this paper
• Overexpression, Amplification, and Androgen Regulation of TPD52 in Prostate Cancer

  2004cited by this paper
• Regulation of KLF5 involves the Sp1 transcription factor in human epithelial cells.

  2004cited by this paper
• The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture

  2004cited by this paper
• Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras

  2004cited by this paper
• Negative regulation of transforming growth factor-β (TGF-β) signaling by WW domain-containing protein 1 (WWP1)

  2004cited by this paper
• Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1).

  2004cited by this paper
• Blood Lipid Mediator Sphingosine 1-Phosphate Potently Stimulates Platelet-derived Growth Factor-A and -B Chain Expression through S1P1-Gi-Ras-MAPK-dependent Induction of Krüppel-like Factor 5*

  2004cited by this paper
• Intestinal Tumor Progression Is Associated with Altered Function of KLF5*

  2004cited by this paper
• All‐trans retinoic acid inhibits proliferation of intestinal epithelial cells by inhibiting expression of the gene encoding Krüppel‐like factor 5

  2004cited by this paper
• PrLZ, a Novel Prostate-Specific and Androgen-Responsive Gene of the TPD52 Family, Amplified in Chromosome 8q21.1 and Overexpressed in Human Prostate Cancer

  2004cited by this paper
• Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients.

  2003cited by this paper
• Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase.

  2003cited by this paper
• Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy

  2003cited by this paper
• Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function.

  2003cited by this paper
• BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets.

  2003cited by this paper
• KLF5 is frequently deleted and down‐regulated but rarely mutated in prostate cancer

  2003cited by this paper
• Positive and Negative Regulation of the Cardiovascular Transcription Factor KLF5 by p300 and the Oncogenic Regulator SET through Interaction and Acetylation on the DNA-Binding Domain

  2003cited by this paper
• Interactions of β and γENaC with Nedd4 Can Be Facilitated by an ERK-mediated Phosphorylation*

  2002cited by this paper
• Lysine-independent ubiquitination of Epstein-Barr virus LMP2A.

  2002cited by this paper
• The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells

  2002cited by this paper
• Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation.

  2002cited by this paper
• Molecular basis of the VHL hereditary cancer syndrome

  2002cited by this paper
• A possible tumor suppressor role of the KLF5 transcription factor in human breast cancer

  2002cited by this paper
• Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer cells to androgen deprivation

  2002cited by this paper
• Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling

  2002cited by this paper
• Lung Krüppel-like Factor Contains an Autoinhibitory Domain That Regulates Its Transcriptional Activation by Binding WWP1, an E3 Ubiquitin Ligase*

  2001cited by this paper
• Abnormal Expression of MDM2 in Prostate Carcinoma

  2001cited by this paper
• Mechanisms underlying ubiquitination.

  2001cited by this paper
• Intestinal-enriched Krüppel-like Factor (Krüppel-like Factor 5) Is a Positive Regulator of Cellular Proliferation*

  2001cited by this paper
• Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity*

  2000cited by this paper
• Regulation of the cardiac voltage‐gated Na+ channel (H1) by the ubiquitin‐protein ligase Nedd4

  2000cited by this paper
• Positive- and negative-acting Kruppel-like transcription factors bind a transforming growth factor beta control element required for expression of the smooth muscle cell differentiation marker SM22alpha in vivo.

  2000cited by this paper
• Mapping the amplification of EIF3S3 in breast and prostate cancer

  2000cited by this paper
• Positive- and Negative-acting Krüppel-like Transcription Factors Bind a Transforming Growth Factor β Control Element Required for Expression of the Smooth Muscle Cell Differentiation Marker SM22α in Vivo *

  2000cited by this paper
• Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions.

  1999cited by this paper
• BTEB2, a Krüppel-like transcription factor, regulates expression of the SMemb/Nonmuscle myosin heavy chain B (SMemb/NMHC-B) gene.

  1999cited by this paper
• Transcriptional activation of the zinc finger transcription factor BTEB2 gene by Egr-1 through mitogen-activated protein kinase pathways in vascular smooth muscle cells.

  1999cited by this paper
• DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies.

  1998cited by this paper
• Physical and functional interactions between the transactivation domain of the hematopoietic transcription factor NF-E2 and WW domains.

  1998cited by this paper
• Protein ubiquitination involving an E1–E2–E3 enzyme ubiquitin thioester cascade

  1995cited by this paper
• Bmc Developmental Biology Identification of Wnt Responsive Genes Using a Murine Mammary Epithelial Cell Line Model System

  year unknowncited by this paper

• Portrait of WWP1: the current state in human cancer

  2025cites this paper
• Role and therapeutic potential of the NEDD4 family in breast cancer

  2025cites this paper
• Oestrogen inhibition of apoptosis causes upregulation of KLF5 and poor prognosis in female non-small cell lung cancer patients

  2025cites this paper
• CYYR1 promotes the degradation of the E3 ubiquitin ligase WWP1 and is associated with favorable prognosis in breast cancer

  2024cites this paper
• KLF5 inhibition initiates epithelial-mesenchymal transition in non-transformed human squamous epithelial cells.

  2024cites this paper
• The role of NEDD4 related HECT-type E3 ubiquitin ligases in defective autophagy in cancer cells: molecular mechanisms and therapeutic perspectives

  2023cites this paper
• Targeted Protein Degradation: Principles and Applications of the Proteasome

  2023cites this paper
• KLF5 and p53 comprise an incoherent feed-forward loop directing cell-fate decisions following stress

  2023cites this paper
• Krüppel-like Factors 4 and 5 in Colorectal Tumorigenesis

  2023cites this paper
• WWP1 E3 ligase at the crossroads of health and disease

  2023cites this paper
• New Insights into KLFs and SOXs in Cancer Pathogenesis, Stemness, and Therapy.

  2023cites this paper
• Molecular mechanism of WWP1‐mediated ubiquitination modification affecting proliferation and invasion/migration of liver cancer cells

  2023cites this paper
• Identification of key genes related to intramuscular fat deposition in Beijing-You chicken by mRNA and miRNA transcriptome analysis

  2023cites this paper
• Mitochondria-originated redox signalling regulates KLF-1 to promote longevity in Caenorhabditis elegans

  2022influential citation
• α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer

  2022cites this paper
• Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer

  2022cites this paper
• Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy.

  2022cites this paper
• STAMBPL1 promotes breast cancer cell resistance to cisplatin partially by stabilizing MKP-1 expression

  2022cites this paper
• WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein

  2021cites this paper
• BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression.

  2021cites this paper
• Roles of Krüppel‐like factor 5 in kidney disease

  2021cites this paper
• Current knowledge of Krüppel-like factor 5 and vascular remodeling: providing insights for therapeutic strategies

  2021cites this paper
• miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/β-catenin signaling pathway

  2021cites this paper
• KLF5, a Novel Therapeutic Target in Squamous Cell Carcinoma

  2021cites this paper
• Post-Translational Modifications That Drive Prostate Cancer Progression

  2021influential citation
• Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

  2021cites this paper
• MicroRNA-145-5p modulates KLF5 and inhibits the migration and invasion in nasopharyngeal carcinoma

  2021cites this paper
• The emerging role of WWP1 in cancer development and progression

  2021influential citation
• A HECT domain ubiquitin ligase CgWWP1 regulates granulocytes proliferation in oyster Crassostrea gigas.

  2021cites this paper
• miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/β-catenin signaling pathway

  2021cites this paper
• Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer

  2021cites this paper
• The roles and regulation of the KLF5 transcription factor in cancers

  2021cites this paper
• Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

  2020cites this paper
• WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

  2020cites this paper
• WWP2 Promotes Odontoblastic Differentiation by Monoubiquitinating KLF5

  2020cites this paper
• Distinct p63 and p73 Protein Interactions Predict Specific Functions in mRNA Splicing and Polyploidy Control in Epithelia

  2020cites this paper
• USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5

  2019cites this paper
• Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.

  2019cites this paper
• HECT-Type E3 Ubiquitin Ligases in Cancer.

  2019cites this paper
• Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes.

  2019cites this paper
• USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5

  2019influential citation
• Ubiquitin Mediated Posttranslational Modification of Proteins Involved in Various Signaling Diseases

  2019cites this paper
• The role of E3 ubiquitin ligase HECTD3 in cancer and beyond

  2019cites this paper
• β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin.

  2018cites this paper
• HDAC-mediated deacetylation of KLF5 associates with its proteasomal degradation.

  2018influential citation
• CINP is a novel cofactor of KLF5 required for its role in the promotion of cell proliferation, survival and tumor growth

  2018cites this paper
• DNMT1-maintained hypermethylation of Krüppel-like factor 5 involves in the progression of clear cell renal cell carcinoma

  2017cites this paper
• Mechanism of ubiquitin chain synthesis employed by a HECT domain ubiquitin ligase

  2017cites this paper
• KLF5 promotes cell migration by up‐regulating FYN in bladder cancer cells

  2016cites this paper
• Characterization and phylogenetic analysis of Krüppel-like transcription factor (KLF) gene family in tree shrews (Tupaia belangeri chinensis)

  2016cites this paper
• Cardiomyocyte-specific overexpression of the ubiquitin ligase Wwp1 contributes to reduction in Connexin 43 and arrhythmogenesis.

  2015cites this paper
• Fitting WWP-1 in the dietary restriction network

  2015cites this paper
• Targeting Krüppel-like factor 5 (KLF5) for cancer therapy.

  2015cites this paper
• Molecular functions of NEDD4 E3 ubiquitin ligases in cancer.

  2015cites this paper
• Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds.

  2015cites this paper
• Roles of Klf5 Acetylation in the Self-Renewal and the Differentiation of Mouse Embryonic Stem Cells

  2015cites this paper
• Human cancer: is it linked to dysfunctional lipid metabolism?

  2015cites this paper
• KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation

  2015cites this paper
• Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5)

  2015cites this paper
• BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5

  2015cites this paper
• The interplay between TEAD4 and KLF5 promotes breast cancer partially through inhibiting the transcription of p27Kip1

  2015cites this paper
• Knockdown of WWP1 inhibits growth and invasion, but induces apoptosis of osteosarcoma cells.

  2015cites this paper
• Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer*

  2015cites this paper
• A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma

  2015cites this paper
• Functional and Clinical Evidence That TAZ is a Candidate Oncogene in Hepatocellular Carcinoma

  2015cites this paper
• Caractérisation d'un nouveau mécanisme d'action de la E3 ubiquitine ligase WWP1 et régulation de son activité dans la cancérogenèse

  2015cites this paper
• A Krüppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans

  2014cites this paper
• WWOX suppresses KLF5 expression and breast cancer cell growth.

  2014cites this paper
• Curcumin Promotes KLF5 Proteasome Degradation through Downregulating YAP/TAZ in Bladder Cancer Cells

  2014cites this paper
• FBW7-mediated ubiquitination and degradation of KLF5 REVIEW World Journal of Biological Chemistry

  2014cites this paper
• Krüppel-like factors, chromatin, and epigenetics: new frontiers in understanding the regulation of complex diseases

  2014cites this paper
• Crosstalk between kinases and Nedd4 family ubiquitin ligases.

  2014cites this paper
• FBW7-mediated ubiquitination and degradation of KLF5.

  2014cites this paper
• Pharmaceutical perspectives of HECT-type ubiquitin ligase Smurf1.

  2013cites this paper
• E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation.

  2013cites this paper
• Role of KLF5 in hormonal signaling and breast cancer development.

  2013cites this paper
• Different Expression Patterns and Functions of Acetylated and Unacetylated Klf5 in the Proliferation and Differentiation of Prostatic Epithelial Cells

  2013cites this paper
• Krüppel-like factors in cancer

  2013cites this paper
• Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration

  2013cites this paper
• The double life of KLF5: Opposing roles in regulation of gene‐expression, cellular function, and transformation

  2013cites this paper
• The Role of the HECT-Type Ubiquitin Ligases WWP1 and WWP2 in Nerve Cell Development and Function

  2012cites this paper
• Fbw7γ-mediated degradation of KLF13 prevents RANTES expression in resting human but not murine T lymphocytes.

  2012cites this paper
• The WWP1 ubiquitin E3 ligase increases TRAIL resistance in breast cancer

  2012cites this paper
• Krüppel-like Factor 11 Regulates the Expression of Metabolic Genes via an Evolutionarily Conserved Protein Interaction Domain Functionally Disrupted in Maturity Onset Diabetes of the Young

  2012cites this paper
• WW domain-containing proteins: retrospectives and the future.

  2012cites this paper
• Tumorigenesis and Neoplastic Progression YAP Promotes Breast Cell Proliferation and Survival Partially through Stabilizing the KLF 5 Transcription Factor

  2012influential citation
• Krüppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens.

  2012cites this paper
• YAP promotes breast cell proliferation and survival partially through stabilizing the KLF5 transcription factor.

  2012cites this paper
• New insights to the ubiquitin–proteasome pathway (UPP) mechanism during spermatogenesis

  2012cites this paper
• TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis.

  2012influential citation
• Ubiquitin-Mediated Degradation Proliferation by Targeting the Tumor Suppressor p21 for E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell

  2012cites this paper
• The ubiquitin E3 ligase WWP1 decreases CXCL12-mediated MDA231 breast cancer cell migration and bone metastasis.

  2012cites this paper
• Ezrin Ubiquitylation by the E3 Ubiquitin Ligase, WWP1, and Consequent Regulation of Hepatocyte Growth Factor Receptor Activity

  2012cites this paper
• Association of Expression of Kruppel-Like Factor 4 and Kruppel-Like Factor 5 with the Clinical Manifestations of Breast Cancer

  2012cites this paper
• Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP.

  2012cites this paper
• Expression of Krűppel-like factor 5 in gastric cancer and its clinical correlation in Taiwan

  2011cites this paper
• WWP1: a versatile ubiquitin E3 ligase in signaling and diseases

  2011cites this paper
• WW Domain-containing E3 Ubiquitin Protein Ligase 1 (WWP1) Delays Cellular Senescence by Promoting p27Kip1 Degradation in Human Diploid Fibroblasts*

  2011cites this paper
• The role of HECT type ubiquitin E3 ligases WWP1 and WWP2 in nerve cell development and function

  2011cites this paper
• WWP1 (WW domain containing E3 ubiquitin protein ligase 1)

  2011cites this paper