title: Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148.
abstract: The E3 ubiquitin ligase Smurf1 targets the master regulator of osteoblast differentiation, Runx2, for degradation, yet the function of Smurf1, if any, during osteoblast differentiation in vivo is ill defined. Here, we show that Smurf1 prevents osteoblast differentiation by decreasing Runx2 accumulation in osteoblasts. Remarkably, mice harboring a substitution mutation at serine 148 (S148) in Smurf1 that prevents its phosphorylation by AMPK (Smurf1(ki/ki)) display a premature osteoblast differentiation phenotype that is equally severe as that of Smurf1(-/-) mice, as well as a high bone mass, and are also hyperinsulinemic and hypoglycemic. Consistent with the fact that Smurf1 targets the insulin receptor for degradation, there is, in Smurf1(ki/ki) mice, an increase in insulin signaling in osteoblasts that triggers a rise in the circulating levels of osteocalcin, a hormone that favors insulin secretion. These results identify Smurf1 as a determinant of osteoblast differentiation during the development of bone formation and glucose homeostasis post-natally and demonstrate the necessity of S148 for these functions.
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Shimazu
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: gk2172@columbia.edu.
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007003:Hypoglycemia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D011972:Receptor, Insulin / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D015675:Osteocalcin; D012694:Serine; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011972:Receptor, Insulin; D005947:Glucose