ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability.
Rho kinases belong to a family of serine/threonine kinases whose role in recruitment and migration of inflammatory cells is poorly understood. We show that deficiency of ROCK1 results in increased recruitment and migration of macrophages and neutrophils in vitro and in vivo. Enhanced migration resulting from ROCK1 deficiency is observed despite normal expression of ROCK2 and a significant reduction in overall ROCK activity. ROCK1 directly binds PTEN in response to receptor activation and is essential for PTEN phosphorylation and stability. In the absence of ROCK1, PTEN phosphorylation, stability, and its activity are significantly impaired. Consequently, increased activation of downstream targets of PTEN, including PIP3, AKT, GSK-3beta, and cyclin D1, is observed. Our results reveal ROCK1 as a physiologic regulator of PTEN whose function is to repress excessive recruitment of macrophages and neutrophils during acute inflammation.
Vemula
Sasidhar
S
Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, USA. svemula@iupui.edu
Shi
Jianjian
J
Hanneman
Philip
P
Wei
Lei
L
Kapur
Reuben
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009504:Neutrophils / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000378:metabolism*; D010538:Peritonitis / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology; D054460:rho-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000199:Actins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse