| First Author | Steury MD | Year | 2017 |
| Journal | Biochem J | Volume | 474 |
| Issue | 14 | Pages | 2301-2313 |
| PubMed ID | 28572156 | Mgi Jnum | J:247008 |
| Mgi Id | MGI:5925186 | Doi | 10.1042/BCJ20170093 |
| Citation | Steury MD, et al. (2017) G-protein-coupled receptor kinase-2 is a critical regulator of TNFalpha signaling in colon epithelial cells. Biochem J 474(14):2301-2313 |
| abstractText | G-protein-coupled receptor kinase-2 (GRK2) belongs to the GRK family of serine/threonine protein kinases critical in the regulation of G-protein-coupled receptors. Apart from this canonical role, GRK2 is also involved in several signaling pathways via distinct intracellular interactomes. In the present study, we examined the role of GRK2 in TNFalpha signaling in colon epithelial cell-biological processes including wound healing, proliferation, apoptosis, and gene expression. Knockdown of GRK2 in the SW480 human colonic cells significantly enhanced TNFalpha-induced epithelial cell wound healing without any effect on apoptosis/proliferation. Consistent with wound-healing effects, GRK2 knockdown augmented TNFalpha-induced matrix metalloproteinases (MMPs) 7 and 9, as well as urokinase plasminogen activator (uPA; factors involved in cell migration and wound healing). To assess the mechanism by which GRK2 affects these physiological processes, we examined the role of GRK2 in TNFalpha-induced MAPK and NF-kappaB pathways. Our results demonstrate that while GRK2 knockdown inhibited TNFalpha-induced IkappaBalpha phosphorylation, activation of ERK was significantly enhanced in GRK2 knockdown cells. Our results further demonstrate that GRK2 inhibits TNFalpha-induced ERK activation by inhibiting generation of reactive oxygen species (ROS). Together, these data suggest that GRK2 plays a critical role in TNFalpha-induced wound healing by modulating MMP7 and 9 and uPA levels via the ROS-ERK pathway. Consistent with in vitro findings, GRK2 heterozygous mice exhibited enhanced intestinal wound healing. Together, our results identify a novel role for GRK2 in TNFalpha signaling in intestinal epithelial cells. |
