XB-ART-54831
J Biol Chem
January 1, 2018;
293
(22):
8342-8361.
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The atypical mitogen-activated protein kinase ERK3 is essential for establishment of epithelial architecture.
Abstract
Epithelia contribute to physical barriers that protect internal tissues from the external environment and also support organ structure. Accordingly, establishment and maintenance of epithelial architecture are essential for both embryonic development and adult physiology. Here, using gene knockout and knockdown techniques along with gene profiling, we show that extracellular signal-regulated kinase 3 (ERK3), a poorly characterized atypical mitogen-activated protein kinase (MAPK), regulates the epithelial architecture in vertebrates. We found that in Xenopus embryonic epidermal epithelia, ERK3 knockdown impairs adherens and tight-junction protein distribution, as well as tight-junction barrier function, resulting in epidermal breakdown. Moreover, in human epithelial breast cancer cells, inhibition of ERK3 expression induced thickened epithelia with aberrant adherens and tight junctions. Results from microarray analyses suggested that transcription factor AP-2α (TFAP2A), a transcriptional regulator important for epithelial gene expression, is involved in ERK3-dependent changes in gene expression. Of note, TFAP2A knockdown phenocopied ERK3 knockdown in both Xenopus embryos and human cells, and ERK3 was required for full activation of TFAP2A-dependent transcription. Our findings reveal that ERK3 regulates epithelial architecture, possibly together with TFAP2A.
PubMed ID: 29674317
PMC ID: PMC5986203
Article link: J Biol Chem
Species referenced: Xenopus laevis
Genes referenced: atp1b1 cdh1 egr4 hinfp klf4 klf5 krt12.1 mapk6 myc nhs odc1 pam sp1 sp2 sp3 tfap2a tfap2b tfap2c tfcp2l1 zeb1 zfx zic1 zic3 zic4
GO keywords: MAP kinase activity [+]
establishment or maintenance of polarity of embryonic epithelium
regulation of epithelial cell differentiation
cell junction maintenance
Antibodies: Acta1 Ab9 Cdh1 Ab1 Mapk6 Ab1 Myc Ab5 Tjp1 Ab1 V5 Ab3
Morpholinos: mapk6 MO1 mapk6 MO2 mapk6 MO3 tfap2a MO3 tfap2a MO4
Disease Ontology terms: branchiooculofacial syndrome
OMIMs: BRANCHIOOCULOFACIAL SYNDROME; BOFS
GEO Series: GSE110427: NCBI
Article Images: [+] show captions
References [+] :
Al-Mahdi,
A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration.
2016, Pubmed
Al-Mahdi,
A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration.
2016,
Pubmed
Batsché, RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. 1998, Pubmed
Behrens, The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. 1992, Pubmed
Bello, A function for dystroglycan in pronephros development in Xenopus laevis. 2008, Pubmed , Xenbase
Bian, ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells. 2017, Pubmed
Bosher, The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. 1995, Pubmed
Brewer, Loss of AP-2alpha impacts multiple aspects of ventral body wall development and closure. 2004, Pubmed
Cargnello, Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. 2011, Pubmed
Cizelsky, The Wnt/JNK signaling target gene alcam is required for embryonic kidney development. 2014, Pubmed , Xenbase
Costantini, Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. 2010, Pubmed
Coulombe, Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation. 2003, Pubmed
Coulombe, Atypical mitogen-activated protein kinases: structure, regulation and functions. 2007, Pubmed
Decary, The retinoblastoma protein binds the promoter of the survival gene bcl-2 and regulates its transcription in epithelial cells through transcription factor AP-2. 2002, Pubmed
Desgrange, Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies. 2015, Pubmed , Xenbase
Ding, Detection of tight junction barrier function in vivo by biotin. 2011, Pubmed , Xenbase
Eckert, The AP-2 family of transcription factors. 2006, Pubmed
El-Brolosy, Genetic compensation: A phenomenon in search of mechanisms. 2017, Pubmed
Hennig, Mechanisms identified in the transcriptional control of epithelial gene expression. 1996, Pubmed
Howland, On the Effect of Removal of the Pronephros of the Amphibian Embryo. 2006, Pubmed
Julien, Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression. 2004, Pubmed
Klinger, Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality. 2009, Pubmed
Kostenko, Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5. 2012, Pubmed
Leask, Transcription factor AP2 and its role in epidermal-specific gene expression. 1991, Pubmed
Liang, Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. 2005, Pubmed
Lienkamp, Using Xenopus to study genetic kidney diseases. 2016, Pubmed , Xenbase
Long, ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. 2012, Pubmed
Luo, Transcription factor AP-2 is an essential and direct regulator of epidermal development in Xenopus. 2002, Pubmed , Xenbase
Marciano, A holey pursuit: lumen formation in the developing kidney. 2018, Pubmed
Matsuda, A New Nomenclature of Xenopus laevis Chromosomes Based on the Phylogenetic Relationship to Silurana/Xenopus tropicalis. 2015, Pubmed , Xenbase
Milunsky, TFAP2A mutations result in branchio-oculo-facial syndrome. 2008, Pubmed
Milunsky, Genotype-phenotype analysis of the branchio-oculo-facial syndrome. 2011, Pubmed
Moody, Segregation of fate during cleavage of frog (Xenopus laevis) blastomeres. 1991, Pubmed , Xenbase
Rai, Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma. 2004, Pubmed
Ran, Genome engineering using the CRISPR-Cas9 system. 2014, Pubmed
Schorle, Transcription factor AP-2 essential for cranial closure and craniofacial development. 1996, Pubmed
Schumacher, Scaffolding by ERK3 regulates MK5 in development. 2005, Pubmed
Session, Genome evolution in the allotetraploid frog Xenopus laevis. 2016, Pubmed , Xenbase
Seternes, Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. 2005, Pubmed
Sinha, Defining the regulatory factors required for epidermal gene expression. 2000, Pubmed
Slaymaker, Rationally engineered Cas9 nucleases with improved specificity. 2016, Pubmed
Snape, Transcription factor AP-2 is tissue-specific in Xenopus and is closely related or identical to keratin transcription factor 1 (KTF-1). 1992, Pubmed , Xenbase
Sun, Xenopus Claudin-6 is required for embryonic pronephros morphogenesis and terminal differentiation. 2015, Pubmed , Xenbase
Wang, AP-2alpha: a regulator of EGF receptor signaling and proliferation in skin epidermis. 2006, Pubmed
Wang, AP-2 factors act in concert with Notch to orchestrate terminal differentiation in skin epidermis. 2008, Pubmed
Williams, Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. 1991, Pubmed
Williams, Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements. 1989, Pubmed
Zhang, Expression of TFAP2beta and TFAP2gamma genes in Xenopus laevis. 2006, Pubmed , Xenbase
Zhang, Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. 1996, Pubmed
Batsché, RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. 1998, Pubmed
Behrens, The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. 1992, Pubmed
Bello, A function for dystroglycan in pronephros development in Xenopus laevis. 2008, Pubmed , Xenbase
Bian, ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells. 2017, Pubmed
Bosher, The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. 1995, Pubmed
Brewer, Loss of AP-2alpha impacts multiple aspects of ventral body wall development and closure. 2004, Pubmed
Cargnello, Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. 2011, Pubmed
Cizelsky, The Wnt/JNK signaling target gene alcam is required for embryonic kidney development. 2014, Pubmed , Xenbase
Costantini, Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. 2010, Pubmed
Coulombe, Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation. 2003, Pubmed
Coulombe, Atypical mitogen-activated protein kinases: structure, regulation and functions. 2007, Pubmed
Decary, The retinoblastoma protein binds the promoter of the survival gene bcl-2 and regulates its transcription in epithelial cells through transcription factor AP-2. 2002, Pubmed
Desgrange, Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies. 2015, Pubmed , Xenbase
Ding, Detection of tight junction barrier function in vivo by biotin. 2011, Pubmed , Xenbase
Eckert, The AP-2 family of transcription factors. 2006, Pubmed
El-Brolosy, Genetic compensation: A phenomenon in search of mechanisms. 2017, Pubmed
Hennig, Mechanisms identified in the transcriptional control of epithelial gene expression. 1996, Pubmed
Howland, On the Effect of Removal of the Pronephros of the Amphibian Embryo. 2006, Pubmed
Julien, Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression. 2004, Pubmed
Klinger, Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality. 2009, Pubmed
Kostenko, Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5. 2012, Pubmed
Leask, Transcription factor AP2 and its role in epidermal-specific gene expression. 1991, Pubmed
Liang, Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. 2005, Pubmed
Lienkamp, Using Xenopus to study genetic kidney diseases. 2016, Pubmed , Xenbase
Long, ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. 2012, Pubmed
Luo, Transcription factor AP-2 is an essential and direct regulator of epidermal development in Xenopus. 2002, Pubmed , Xenbase
Marciano, A holey pursuit: lumen formation in the developing kidney. 2018, Pubmed
Matsuda, A New Nomenclature of Xenopus laevis Chromosomes Based on the Phylogenetic Relationship to Silurana/Xenopus tropicalis. 2015, Pubmed , Xenbase
Milunsky, TFAP2A mutations result in branchio-oculo-facial syndrome. 2008, Pubmed
Milunsky, Genotype-phenotype analysis of the branchio-oculo-facial syndrome. 2011, Pubmed
Moody, Segregation of fate during cleavage of frog (Xenopus laevis) blastomeres. 1991, Pubmed , Xenbase
Rai, Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma. 2004, Pubmed
Ran, Genome engineering using the CRISPR-Cas9 system. 2014, Pubmed
Schorle, Transcription factor AP-2 essential for cranial closure and craniofacial development. 1996, Pubmed
Schumacher, Scaffolding by ERK3 regulates MK5 in development. 2005, Pubmed
Session, Genome evolution in the allotetraploid frog Xenopus laevis. 2016, Pubmed , Xenbase
Seternes, Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. 2005, Pubmed
Sinha, Defining the regulatory factors required for epidermal gene expression. 2000, Pubmed
Slaymaker, Rationally engineered Cas9 nucleases with improved specificity. 2016, Pubmed
Snape, Transcription factor AP-2 is tissue-specific in Xenopus and is closely related or identical to keratin transcription factor 1 (KTF-1). 1992, Pubmed , Xenbase
Sun, Xenopus Claudin-6 is required for embryonic pronephros morphogenesis and terminal differentiation. 2015, Pubmed , Xenbase
Wang, AP-2alpha: a regulator of EGF receptor signaling and proliferation in skin epidermis. 2006, Pubmed
Wang, AP-2 factors act in concert with Notch to orchestrate terminal differentiation in skin epidermis. 2008, Pubmed
Williams, Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. 1991, Pubmed
Williams, Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements. 1989, Pubmed
Zhang, Expression of TFAP2beta and TFAP2gamma genes in Xenopus laevis. 2006, Pubmed , Xenbase
Zhang, Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. 1996, Pubmed