Faculty Collaboration Database

Hepatic Stellate Cell Selective Disruption of Dynamin-2 GTPase Increases Murine Fibrogenesis through Up-Regulation of Sphingosine-1 Phosphate-Induced Cell Migration. Am J Pathol 2017 Jan;187(1):134-145

Date

11/15/2016

Pubmed ID

27840081

Pubmed Central ID

PMC5225297

DOI

10.1016/j.ajpath.2016.09.001

Scopus ID

2-s2.0-85006355344 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Dynamin-2 (Dyn2) is implicated in endocytosis of receptor tyrosine kinases, which contribute to hepatic stellate cell (HSC) activation and liver fibrosis. A point mutation converting lysine 44 of Dyn2 to alanine (Dyn2K44A) disrupts its GTPase activity. We hypothesized that Dyn2K44A expression in HSCs would decrease HSC activation and fibrogenesis in vivo by disrupting receptor tyrosine kinase endocytosis and signaling. Dyn2K44A^fl/fl mice were crossed with Collagen1-Cre (Col1^Cre) mice to generate offspring with HSC selective expression of Dyn2K44A (Col1^Cre/Dyn2K44A^fl/fl). Contrary to our hypothesis, Col1^Cre/Dyn2K44A^fl/fl mice showed increased hepatic fibrosis in response to liver injury. To elucidate mechanisms, we conducted in vitro experiments with HSCs infected with adenoviral vectors encoding LacZ, Dyn2K44A, or Dyn2WT. HSC-expressing Dyn2K44A displayed increased mRNA and protein levels of sphingosine kinase-1 (SK1), an enzyme previously implicated in the pathogenesis of fibrosis. To study the functional effects of Dyn2K44A regulation of SK1, we examined effects of AKT signaling and migration in HSCs. Dyn2K44A promoted both AKT phosphorylation and HSC migration in an SK1-dependent manner. Genetic disruption of Dyn2 GTPase activity selectively in HSC enhances fibrogenesis, driven at least in part through up-regulation of the SK1 pathway and cell migration in HSCs.

Author List

Wang R, Ding Q, De Assuncao TM, Mounajjed T, Maiers JL, Dou C, Cao S, Yaqoob U, Huebert RC, Shah VH

Author

Thiago Milech De Assuncao Research Scientist II in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bile Ducts
Carbon Tetrachloride
Cell Movement
Collagen Type I
Dynamin II
Hepatic Stellate Cells
Ligation
Liver Cirrhosis
Lysophospholipids
Mice
Mutant Proteins
Phosphotransferases (Alcohol Group Acceptor)
Proto-Oncogene Proteins c-akt
Signal Transduction
Sphingosine
Up-Regulation