Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 276 (12): 9406-9412

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Activation of Serum- and Glucocorticoid-induced Protein Kinase (Sgk) by Cyclic AMP and Insulin*

Nicola Perrotti{ddagger}§, Ruth A. He{ddagger}, Susan A. Phillips{ddagger}, Carol Renfrew Haft{ddagger}, , and Simeon I. Taylor{ddagger}

From the {ddagger}Diabetes Branch, Division of Intramural Research, NIDDK, Bethesda, Maryland 20892 and the §Dipartimento di Medicina Sperimentale e Clinica "Gaetano Salvatore," Università di Catanzaro, Catanzaro 88100, Italy

ABSTRACT Back to Top

Abstract: Sgk (serum- and glucocorticoid-induced protein kinase) is a serine/threonine-specific protein kinase that is transcriptionally regulated by serum, glucorticoids, and mineralocorticoids. Sgk regulates the amiloride-sensitive sodium channel in kidney principal cells. Insulin and insulin-like growth factor-1 stimulate activity of Sgk by a mechanism mediated by phosphoinositide-dependent kinases (PDK)-1 and -2. In this study, we demonstrate that incubation of transfected cells with 8-(4-chlorophenylthio)-cAMP (8CPT-cAMP; 0.2 mM) led to a 2-fold activation of recombinant Sgk expressed in COS7 cells. Furthermore, the combination of insulin plus 8CPT-cAMP elicited a larger response than either agent alone. The effect of insulin was inhibited by wortmannin (100 nM), but not by the cyclic AMP-dependent protein kinase (PKA) inhibitor, H89 (10 μM). As expected, the effect of 8CPT-cAMP was completely blocked by H89. Surprisingly, the effect of 8CPT-cAMP was also inhibited by wortmannin, suggesting that phosphorylation of Sgk by PDK-1 and/or -2 is required for activation by 8CPT-cAMP. Mutational analysis led to similar conclusions. The Thr369 -> Ala mutant, lacking the PKA phosphorylation site, was activated by insulin but not 8CPT-cAMP. In contrast, the Ser422 -> Ala mutant, lacking a PDK-2 phosphorylation site, was inactive and resistant to activation by either insulin or 8CPT-cAMP. In summary, Sgk is subject to complex regulatory mechanisms. In addition to regulation at the level of gene expression, the enzymatic activity of Sgk is regulated by multiple protein kinases, including PKA, PDK-1, and PDK-2. Cross-talk among these signaling pathways may play an important role in the pathogenesis of the hypertension associated with hyperinsulinemia, obesity, and insulin resistance.

Received for publication August 4, 2000. Revision received November 9, 2000.

Quantitative phosphoproteomics in nuclei of vasopressin-sensitive renal collecting duct cells.
S. J. Bolger, P. A. G. Hurtado, J. D. Hoffert, F. Saeed, T. Pisitkun, and M. A. Knepper (2012)
Am J Physiol Cell Physiol 303, C1006-C1020
   Abstract »    Full Text »    PDF »
cAMP Stimulates Apical Exocytosis of the Renal Na+-K+-2Cl- Cotransporter NKCC2 in the Thick Ascending Limb: ROLE OF PROTEIN KINASE A.
P. S. Caceres, G. R. Ares, and P. A. Ortiz (2009)
J. Biol. Chem. 284, 24965-24971
   Abstract »    Full Text »    PDF »
SGK1 Phosphorylation of I{kappa}B Kinase {alpha} and p300 Up-regulates NF-{kappa}B Activity and Increases N-Methyl-D-aspartate Receptor NR2A and NR2B Expression.
D. J. C. Tai, C.-C. Su, Y.-L. Ma, and E. H. Y. Lee (2009)
J. Biol. Chem. 284, 4073-4089
   Abstract »    Full Text »    PDF »
Serum and glucocorticoid regulated kinase and disturbed renal sodium transport in diabetes.
C. E Hills, P. E Squires, and R. Bland (2008)
J. Endocrinol. 199, 343-349
   Abstract »    Full Text »    PDF »
Corticotropin-releasing hormone stimulates SGK-1 kinase expression in cultured hippocampal neurons via CRH-R1.
H. Sheng, T. Sun, B. Cong, P. He, Y. Zhang, J. Yan, C. Lu, and X. Ni (2008)
Am J Physiol Endocrinol Metab 295, E938-E946
   Abstract »    Full Text »    PDF »
Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo.
D. K. Coletta, B. Balas, A. O. Chavez, M. Baig, M. Abdul-Ghani, S. R. Kashyap, F. Folli, D. Tripathy, L. J. Mandarino, J. E. Cornell, et al. (2008)
Am J Physiol Endocrinol Metab 294, E910-E917
   Abstract »    Full Text »    PDF »
Epithelial Na+ Channel Stimulation by n-3 Fatty Acids Requires Proximity to a Membrane-bound A-kinase-anchoring Protein Complexed with Protein Kinase A and Phosphodiesterase.
F. Mies, C. Spriet, L. Heliot, and S. Sariban-Sohraby (2007)
J. Biol. Chem. 282, 18339-18347
   Abstract »    Full Text »    PDF »
Nongenomic Actions of Aldosterone on the Renal Tubule.
D. W. Good (2007)
Hypertension 49, 728-739
   Full Text »    PDF »
Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor.
D. Wang, H. Zhang, F. Lang, and C. C. Yun (2007)
Am J Physiol Cell Physiol 292, C396-C404
   Abstract »    Full Text »    PDF »
(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms..
F. Lang, C. Bohmer, M. Palmada, G. Seebohm, N. Strutz-Seebohm, and V. Vallon (2006)
Physiol Rev 86, 1151-1178
   Abstract »    Full Text »    PDF »
Regulation of Surface Localization of the Small Conductance Ca2+-activated Potassium Channel, Sk2, through Direct Phosphorylation by cAMP-dependent Protein Kinase.
Y. Ren, L. F. Barnwell, J. C. Alexander, F. D. Lubin, J. P. Adelman, P. J. Pfaffinger, L. A. Schrader, and A. E. Anderson (2006)
J. Biol. Chem. 281, 11769-11779
   Abstract »    Full Text »    PDF »
SGK1 Kinase Upregulates GLUT1 Activity and Plasma Membrane Expression.
M. Palmada, C. Boehmer, A. Akel, J. Rajamanickam, S. Jeyaraj, K. Keller, and F. Lang (2006)
Diabetes 55, 421-427
   Abstract »    Full Text »    PDF »
Role of Sgk1 in salt and potassium homeostasis.
V. Vallon, P. Wulff, D. Y. Huang, J. Loffing, H. Volkl, D. Kuhl, and F. Lang (2005)
Am J Physiol Regulatory Integrative Comp Physiol 288, R4-R10
   Abstract »    Full Text »    PDF »
Serum and glucocorticoid-regulated kinase Sgk1 inhibits insulin-dependent activation of phosphomannomutase 2 in transfected COS-7 cells.
M. Menniti, R. Iuliano, R. Amato, R. Boito, M. Corea, I. Le Pera, E. Gulletta, G. Fuiano, and N. Perrotti (2005)
Am J Physiol Cell Physiol 288, C148-C155
   Abstract »    Full Text »    PDF »
Surfing the lipid bilayer: how basolateral insulin receptors regulate Na+ channels in the apical cell membrane. Focus on "Real-time three-dimensional imaging of lipid signal transduction: apical membrane insertion of epithelial Na+ channels".
F. Lang (2004)
Am J Physiol Cell Physiol 287, C1539-C1540
   Full Text »    PDF »
cAMP and Serum and Glucocorticoid-inducible Kinase (SGK) Regulate the Epithelial Na+ Channel through Convergent Phosphorylation of Nedd4-2.
P. M. Snyder, D. R. Olson, R. Kabra, R. Zhou, and J. C. Steines (2004)
J. Biol. Chem. 279, 45753-45758
   Abstract »    Full Text »    PDF »
Low prevalence of nonconservative mutations of serum and glucocorticoid-regulated kinase (SGK1) gene in hypertensive and renal patients.
N. Trochen, S. Ganapathipillai, P. Ferrari, B. M. Frey, and F. J. Frey (2004)
Nephrol. Dial. Transplant. 19, 2499-2504
   Abstract »    Full Text »    PDF »
cAMP-stimulated Na+ transport in H441 distal lung epithelial cells: role of PKA, phosphatidylinositol 3-kinase, and sgk1.
C. P. Thomas, J. R. Campbell, P. J. Wright, and R. F. Husted (2004)
Am J Physiol Lung Cell Mol Physiol 287, L843-L851
   Abstract »    Full Text »    PDF »
A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's {alpha}-Subunit.
A. Diakov and C. Korbmacher (2004)
J. Biol. Chem. 279, 38134-38142
   Abstract »    Full Text »    PDF »
In vitro characterization of aldosterone and cAMP effects in mouse distal convoluted tubule cells.
D. Gonzalez-Nunez, M. Morales-Ruiz, A. Leivas, S. C. Hebert, and E. Poch (2004)
Am J Physiol Renal Physiol 286, F936-F944
   Abstract »    Full Text »    PDF »
Long-term stimulation of alveolar epithelial cells by {beta}-adrenergic agonists: increased Na+ transport and modulation of cell growth?.
Y. Berthiaume (2003)
Am J Physiol Lung Cell Mol Physiol 285, L798-L801
   Full Text »    PDF »
Distribution and regulation of expression of serum- and glucocorticoid-induced kinase-1 in the rat kidney.
D. A. de la Rosa, T. Coric, N. Todorovic, D. Shao, T. Wang, and C. M Canessa (2003)
J. Physiol. 551, 455-466
   Abstract »    Full Text »    PDF »
A Homogeneous Fluorescence Polarization Assay Adaptable for a Range of Protein Serine/Threonine and Tyrosine Kinases.
E. A. Gaudet, K.-S. Huang, Y. Zhang, W. Huang, D. Mark, and J. R. Sportsman (2003)
J Biomol Screen 8, 164-175
   Abstract »    PDF »
Importin-alpha Mediates the Regulated Nuclear Targeting of Serum- and Glucocorticoid-inducible Protein Kinase (Sgk) by Recognition of a Nuclear Localization Signal in the Kinase Central Domain.
A. C. Maiyar, M. L.L. Leong, and G. L. Firestone (2003)
Mol. Biol. Cell 14, 1221-1239
   Abstract »    Full Text »    PDF »
Expression of the Serum- and Glucocorticoid-inducible Protein Kinase, Sgk, Is a Cell Survival Response to Multiple Types of Environmental Stress Stimuli in Mammary Epithelial Cells.
M. L. L. Leong, A. C. Maiyar, B. Kim, B. A. O'Keeffe, and G. L. Firestone (2003)
J. Biol. Chem. 278, 5871-5882
   Abstract »    Full Text »    PDF »
Role of SGK in hormonal regulation of epithelial sodium channel in A6 cells.
D. Alvarez de la Rosa and C. M. Canessa (2003)
Am J Physiol Cell Physiol 284, C404-C414
   Abstract »    Full Text »    PDF »
Mechanism by which cAMP activates PI3-kinase and increases bile acid secretion in WIF-B9 cells.
T. Kagawa, L. Varticovski, Y. Sai, and I. M. Arias (2002)
Am J Physiol Cell Physiol 283, C1655-C1666
   Abstract »    Full Text »    PDF »
Sodium transporter abundance profiling in kidney: effect of spironolactone.
J. Nielsen, T.-H. Kwon, S. Masilamani, K. Beutler, H. Hager, S. Nielsen, and M. A. Knepper (2002)
Am J Physiol Renal Physiol 283, F923-F933
   Abstract »    Full Text »    PDF »
Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways.
C. Shelly and R. Herrera (2002)
J. Cell Sci. 115, 1985-1993
   Abstract »    Full Text »    PDF »
Glucocorticoid Activation of Na+/H+Exchanger Isoform 3 Revisited: THE ROLES OF SGK1 AND NHERF2.
C. C. Yun, Y. Chen, and F. Lang (2002)
J. Biol. Chem. 277, 7676-7683
   Abstract »    Full Text »    PDF »
Yeast Protein Kinases and the RHO1 Exchange Factor TUS1 Are Novel Components of the Cell Integrity Pathway in Yeast.
T. Schmelzle, S. B. Helliwell, and M. N. Hall (2002)
Mol. Cell. Biol. 22, 1329-1339
   Abstract »    Full Text »    PDF »
Regulation and Physiological Roles of Serum- and Glucocorticoid-Induced Protein Kinase Isoforms.
F. Lang and P. Cohen (2001)
Sci. STKE 2001, re17
   Abstract »    Full Text »    PDF »
Serum- and Glucocorticoid-inducible Kinase SGK Phosphorylates and Negatively Regulates B-Raf.
B.-H. Zhang, E. D. Tang, T. Zhu, M. E. Greenberg, A. B. Vojtek, and K.-L. Guan (2001)
J. Biol. Chem. 276, 31620-31626
   Abstract »    Full Text »    PDF »
sgk: an essential convergence point for peptide and steroid hormone regulation of ENaC-mediated Na+ transport.
C. J. Faletti, N. Perrotti, S. I. Taylor, and B. L. Blazer-Yost (2002)
Am J Physiol Cell Physiol 282, C494-C500
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882