Document Detail

The insulin-like growth factor type 1 and insulin-like growth factor type 2/mannose-6-phosphate receptors independently regulate ERK1/2 activity in HEK293 cells.
MedLine Citation:
PMID:  17620336     Owner:  NLM     Status:  MEDLINE    
Insulin-like growth factor types 1 and 2 (IGF-1; IGF-2) and insulin-like peptides are all members of the insulin superfamily of peptide hormones but bind to several distinct classes of membrane receptor. Like the insulin receptor, the IGF-1 receptor is a heterotetrameric receptor tyrosine kinase, whereas the IGF-2/ mannose 6-phosphate receptor is a single transmembrane domain protein that is thought to function primarily as clearance receptors. We recently reported that IGF-1 and IGF-2 stimulate the ERK1/2 cascade by triggering sphingosine kinase-dependent "transactivation" of G protein-coupled sphingosine-1-phosphate receptors. To determine which IGF receptors mediate this effect, we tested seven insulin family peptides, IGF-1, IGF-2, insulin, and insulin-like peptides 3, 4, 6, and 7, for the ability to activate ERK1/2 in HEK293 cells. Only IGF-1 and IGF-2 potently activated ERK1/2. Although IGF-2 was predictably less potent than IGF-1 in activating the IGF-1 receptor, they were equipotent stimulators of ERK1/2. Knockdown of IGF-1 receptor expression by RNA interference reduced the IGF-1 response to a greater extent than the IGF-2 response, suggesting that IGF-2 did not signal exclusively via the IGF-1 receptor. In contrast, IGF-2 receptor knockdown markedly reduced IGF-2-stimulated ERK1/2 phosphorylation, with no effect on the IGF-1 response. As observed previously, both the IGF-1 and the IGF-2 responses were sensitive to pertussis toxin and the sphingosine kinase inhibitor, dimethylsphingosine. These data indicate that endogenous IGF-1 and IGF-2 receptors can independently initiate ERK1/2 signaling and point to a potential physiologic role for IGF-2 receptors in the cellular response to IGF-2.
Hesham M El-Shewy; Mi-Hye Lee; Lina M Obeid; Ayad A Jaffa; Louis M Luttrell
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-07-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-09-03     Completed Date:  2007-11-01     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  26150-7     Citation Subset:  IM    
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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MeSH Terms
Cell Line
Enzyme Activation / drug effects,  physiology
Insulin / metabolism
Insulin-Like Growth Factor I / genetics,  metabolism*,  pharmacology
Insulin-Like Growth Factor II
MAP Kinase Signaling System / drug effects,  physiology*
Mitogen-Activated Protein Kinase 1 / genetics,  metabolism*
Mitogen-Activated Protein Kinase 3 / genetics,  metabolism*
Phosphotransferases (Alcohol Group Acceptor) / genetics,  metabolism
Proteins / metabolism*,  pharmacology
RNA Interference
Receptor, IGF Type 1 / genetics,  metabolism
Receptor, IGF Type 2 / genetics,  metabolism*
Receptors, Lysosphingolipid / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/IGF2 protein, human; 0/Proteins; 0/Receptor, IGF Type 2; 0/Receptors, Lysosphingolipid; 11061-68-0/Insulin; 67763-96-6/Insulin-Like Growth Factor I; 67763-97-7/Insulin-Like Growth Factor II; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase; EC, IGF Type 1; EC Protein Kinase 1; EC Protein Kinase 3

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