title: Dexamethasone-induced cellular tension requires a SGK1-stimulated Sec5-GEF-H1 interaction.
abstract: Dexamethasone, a synthetic glucocorticoid, is often used to induce osteoblast commitment of mesenchymal stem cells (MSCs), and this process requires RhoA-dependent cellular tension. The underlying mechanism is unclear. In this study, we show that dexamethasone stimulates expression of fibronectin and integrin α5 (ITGA5), accompanied by an increase in the interaction of GEF-H1 (also known as ARHGEF2) with Sec5 (also known as EXOC2), a microtubule (MT)-regulated RhoA activator and a component of the exocyst, respectively. Disruption of this interaction abolishes dexamethasone-induced cellular tension and GEF-H1 targeting to focal adhesion sites at the cell periphery without affecting dexamethasone-induced levels of ITGA5 and fibronectin, and the extracellular deposition of fibronectin at adhesion sites is specifically inhibited. We demonstrate that dexamethasone stimulates the expression of serum-glucocorticoid-induced protein kinase 1 (SGK1), which is necessary and sufficient for the induction of the Sec5-GEF-H1 interaction. Given the function of SGK1 in suppressing MT growth, our data suggest that the induction of SGK1 through treatment with dexamethasone alters MT dynamics to increase Sec5-GEF-H1 interactions, which promote GEF-H1 targeting to adhesion sites. This mechanism is essential for the formation of fibronectin fibrils and their attachment to integrins at adhesion sites in order to generate cellular tension.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Hong-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei 11221, Taiwan.
authors.forename: Chih-Hsuan
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Jean-Cheng
authors.initials: JC
authors.lastname: Kuo
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Sung-Sik
authors.initials: SS
authors.lastname: Hur
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Oscar Kuang-Sheng
authors.initials: OK
authors.lastname: Lee
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei 11221, Taiwan zfchang@ym.edu.tw.
authors.forename: Zee-Fen
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003907:Dexamethasone; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D064067:Rho Guanine Nucleotide Exchange Factors; D033921:Vesicular Transport Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C577356:ARHGEF2 protein, human; C470182:EXOC2 protein, human
keywords: Cellular tension; GEF-H1; Glucocorticoid-mediated osteogenesis; SGK1; Sec5