title: JNK regulates compliance-induced adherens junctions formation in epithelial cells and tissues.
abstract: We demonstrate that c-Jun N-terminal kinase (JNK) responds to substrate stiffness and regulates adherens junction (AJ) formation in epithelial cells in 2D cultures and in 3D tissues in vitro and in vivo. Rigid substrates led to JNK activation and AJ disassembly, whereas soft matrices suppressed JNK activity leading to AJ formation. Expression of constitutively active JNK (MKK7-JNK1) induced AJ dissolution even on soft substrates, whereas JNK knockdown (using shJNK) induced AJ formation even on hard substrates. In human epidermis, basal cells expressed phosphorylated JNK but lacked AJ, whereas suprabasal keratinocytes contained strong AJ but lacked phosphorylated JNK. AJ formation was significantly impaired even in the upper suprabasal layers of bioengineered epidermis when prepared with stiffer scaffold or keratinocytes expressing MKK7-JNK1. By contrast, shJNK1 or shJNK2 epidermis exhibited strong AJ even in the basal layer. The results with bioengineered epidermis were in full agreement with the epidermis of jnk1(-/-) or jnk2(-/-) mice. In conclusion, we propose that JNK mediates the effects of substrate stiffness on AJ formation in 2D and 3D contexts in vitro as well as in vivo.
authors.affiliation: Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, the State University of New York, Amherst, NY 14260, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: You
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Padmashali
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Ranganathan
authors.forename: Pedro
authors.initials: P
authors.lastname: Lei
authors.forename: Nomeda
authors.initials: N
authors.lastname: Girnius
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Stelios T
authors.initials: ST
authors.lastname: Andreadis
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human
keywords: Adherens junctions; Bioengineered epidermis; E-cadherin, β-catenin; Human primary keratinocytes; Intercellular interactions; Substrate rigidity; p-c-Jun