|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 279, Issue 36, 38016-38024, September 3, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differential Roles of the Insulin and Insulin-like Growth Factor-I (IGF-I) Receptors in Response to Insulin and IGF-I*
From the Department of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor (insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). Control preadipocytes expressed fewer insulin receptors than IGF-I receptors (20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytes expressed slightly more insulin receptors than IGF-I receptors (120,000 versus 100,000). In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. In IRKO cells, the insulin-dependent increase in phospho-Akt was completely abolished at the lowest dose and reached only 20% of the control stimulation at 10 nM. Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin- and IGF-I-dependent phosphorylation of Akt. Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I.
Received for publication, December 3, 2003 , and in revised form, June 28, 2004.
* This work was supported by National Institutes of Health Grants DK33301 (to C. R. K.) and DK07260 (to A. E.-P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains Fig. 1.
To whom correspondence should be addressed: One Joslin Place, Boston, MA 02215. Tel.: 617-733-2635; Fax: 617-733-2487; E-mail: c.ronald.kahn{at}joslin.harvard.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Kloting, L. Koch, T. Wunderlich, M. Kern, K. Ruschke, W. Krone, J. C. Bruning, and M. Bluher Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth Diabetes, August 1, 2008; 57(8): 2074 - 2082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Masnikosa, A. Nikolic, and O. Nedic Affinity Modulation of Human Placental Insulin and Insulin-Like Growth Factor Receptors by Lectins J. Biochem., June 1, 2008; 143(6): 813 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lotton, D. Rodrigue, C. Elie, A. Rothenbuhler, N. Lahlou, C. Le Stunff, and P. Bougneres Akt Phosphorylation in Lymphocytes Provides an Index of in Vitro Insulin-Like Growth Factor I Sensitivity Associated with Growth Hormone-Induced Growth J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1458 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Perrini, A. Natalicchio, L. Laviola, A. Cignarelli, M. Melchiorre, F. De Stefano, C. Caccioppoli, A. Leonardini, S. Martemucci, G. Belsanti, et al. Abnormalities of Insulin-Like Growth Factor-I Signaling and Impaired Cell Proliferation in Osteoblasts from Subjects with Osteoporosis Endocrinology, March 1, 2008; 149(3): 1302 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kruger, I. Kratchmarova, B. Blagoev, Y.-H. Tseng, C. R. Kahn, and M. Mann Dissection of the insulin signaling pathway via quantitative phosphoproteomics PNAS, February 19, 2008; 105(7): 2451 - 2456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Bezy, C. Vernochet, S. Gesta, S. R. Farmer, and C. R. Kahn TRB3 Blocks Adipocyte Differentiation through the Inhibition of C/EBP{beta} Transcriptional Activity Mol. Cell. Biol., October 1, 2007; 27(19): 6818 - 6831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fulzele, D. J. DiGirolamo, Z. Liu, J. Xu, J. L. Messina, and T. L. Clemens Disruption of the Insulin-like Growth Factor Type 1 Receptor in Osteoblasts Enhances Insulin Signaling and Action J. Biol. Chem., August 31, 2007; 282(35): 25649 - 25658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Denley, J. M. Carroll, G. V. Brierley, L. Cosgrove, J. Wallace, B. Forbes, and C. T. Roberts Jr. Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors Mol. Cell. Biol., May 15, 2007; 27(10): 3569 - 3577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Inagaki, A. Tiulpakov, P. Rubtsov, P. Sverdlova, V. Peterkova, S. Yakar, S. Terekhov, and D. LeRoith A Familial Insulin-Like Growth Factor-I Receptor Mutant Leads to Short Stature: Clinical and Biochemical Characterization J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1542 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Irwin, H. V. Lin, K. J. Motyl, and L. R. McCabe Normal Bone Density Obtained in the Absence of Insulin Receptor Expression in Bone Endocrinology, December 1, 2006; 147(12): 5760 - 5767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Molina-Munoz, M. T. Romero-Avila, and J. A. Garcia-Sainz Insulin-Like Growth Factor-I Induces {alpha}1B-Adrenergic Receptor Phosphorylation through Gss{gamma} and Epidermal Growth Factor Receptor Transactivation Mol. Endocrinol., November 1, 2006; 20(11): 2773 - 2783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Johansson and H. J. Arnqvist Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1124 - E1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Slaaby, L. Schaffer, I. Lautrup-Larsen, A. S. Andersen, A. C. Shaw, I. S. Mathiasen, and J. Brandt Hybrid Receptors Formed by Insulin Receptor (IR) and Insulin-like Growth Factor I Receptor (IGF-IR) Have Low Insulin and High IGF-1 Affinity Irrespective of the IR Splice Variant J. Biol. Chem., September 8, 2006; 281(36): 25869 - 25874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Ogino, K Sakurai, K Yoshiwara, Y. Suzuki, N Ishizuka, N Seki, Y. Suzuki, H Koseki, T Shirasawa, N Hashimoto, et al. Insulin resistance and increased pancreatic {beta}-cell proliferation in mice expressing a mutant insulin receptor (P1195L). J. Endocrinol., September 1, 2006; 190(3): 739 - 747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Raile, J. Klammt, A. Schneider, A. Keller, S. Laue, R. Smith, R. Pfaffle, J. Kratzsch, E. Keller, and W. Kiess Clinical and Functional Characteristics of the Human Arg59Ter Insulin-Like Growth Factor I Receptor (IGF1R) Mutation: Implications for a Gene Dosage Effect of the Human IGF1R J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2264 - 2271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P. Ciaraldi, S. A. Phillips, L. Carter, V. Aroda, S. Mudaliar, and R. R. Henry Effects of the Rapid-Acting Insulin Analog Glulisine on Cultured Human Skeletal Muscle Cells: Comparisons with Insulin and Insulin-Like Growth Factor I J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5551 - 5558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Blanquart, N. Boute, D. Lacasa, and T. Issad Monitoring the Activation State of the Insulin-Like Growth Factor-1 Receptor and Its Interaction with Protein Tyrosine Phosphatase 1B Using Bioluminescence Resonance Energy Transfer Mol. Pharmacol., September 1, 2005; 68(3): 885 - 894. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |