title: A regulated NH2-terminal Sgk1 variant with enhanced function is expressed in the collecting duct.
abstract: Sgk1 is a relatively unstable kinase that regulates epithelial Na(+) transport in the distal nephron of the kidney. We identified a 5' variant alternate transcript of human Sgk1 (Sgk1_v3) that is expressed in the connecting tubule and collecting duct, is regulated by aldosterone and insulin, and is predicted to encode an NH(2)-terminal variant Sgk1 isoform, Sgk1_i3. Sgk1_i3 contains a polybasic motif, KKR, in its NH(2) terminus that regulates ubiquitination and stability of the expressed protein in HEK293 cells. In Fisher rat thyroid, and mpkCCD(c14) cells, Sgk1_i3 had a significantly greater effect on Na(+) transport compared with Sgk1 and its stimulatory effect was dependent on the kinase domain. Sgk1_i3 increased the abundance of cleaved epithelial Na(+) channel (ENaC) subunits at the cell surface, which was inhibited by coexpression of Nedd4-2. Together, the data demonstrate that a renally expressed Sgk1 isoform, Sgk1_i3, shows improved stability, is regulated by insulin and aldosterone, and stimulates ENaC activity when heterologously expressed in collecting duct cells.
authors.affiliation: Dept. of Internal Medicine, Univ. of Iowa, Iowa City, IA 52242, USA.
authors.forename: Nandita S
authors.initials: NS
authors.lastname: Raikwar
authors.forename: Kang Z
authors.initials: KZ
authors.lastname: Liu
authors.forename: Christie P
authors.initials: CP
authors.lastname: Thomas
mesh_terms: D000450:Aldosterone / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D053503:Epithelial Sodium Channels / Q000502:physiology; D014644:Genetic Variation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology*; D007328:Insulin / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D020033:Protein Isoforms / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012964:Sodium / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D007328:Insulin; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D000099184:Serum-Glucocorticoid Regulated Kinases