Microarray analysis of insulin and insulin-like growth factor-1 (IGF-1) receptor signaling reveals the selective up-regulation of the mitogen heparin-binding EGF-like growth factor by IGF-1.
Insulin and insulin-like growth factor-1 (IGF-1) act through highly homologous receptors that engage similar intracellular signaling pathways, yet these hormones serve largely distinct physiological roles in the control of metabolism and growth, respectively. In an attempt to uncover the molecular mechanisms underlying their divergent functions, we compared insulin receptor (IR) and IGF-1 receptor (IGF-1R) regulation of gene expression by microarray analysis, using 3T3-L1 cells expressing either TrkC/IR or TrkC/IGF-1R chimeric receptors to ensure the highly selective activation of each receptor tyrosine kinase. Following stimulation of the chimeric receptors for 4 h, we detected 11 genes to be differentially regulated, of which 10 were up-regulated to a greater extent by the IGF-1R. These included genes involved in adhesion, transcription, transport, and proliferation. The expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen, was markedly increased by IGF-1R but not IR activation. This effect was dependent on MAPK, but not phosphatidylinositol 3-kinase, and did not require an autocrine loop through the epidermal growth factor receptor. HB-EGF mitogenic activity was detectable in the medium of 3T3-L1 preadipocytes expressing activated IGF-1R but not IR, indicating that the transcriptional response is accompanied by a parallel increase in mature HB-EGF protein. The differential abilities of the IR and IGF-1R tyrosine kinases to stimulate the synthesis and release of a growth factor may provide, at least in part, an explanation for the greater role of the IGF-1R in the control of cellular proliferation.
Mulligan
Claire
C
University of Cambridge, Department of Clinical Biochemistry, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom.
Rochford
Justin
J
Denyer
Gareth
G
Stephens
Richard
R
Yeo
Giles
G
Freeman
Thomas
T
Siddle
Kenneth
K
O'Rahilly
Stephen
S
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics*; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D066257:Heparin-binding EGF-like Growth Factor; D007328:Insulin / Q000494:pharmacology*; D061389:Insulin, Regular, Pork; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D020812:Receptor, trkC / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
D004791:Enzyme Inhibitors; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007328:Insulin; D061389:Insulin, Regular, Pork; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; C000006:insulin, neutral; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D020812:Receptor, trkC