The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins

Abstract

Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.

Keywords

P70-S6 Kinase 1BiologyPI3K/AKT/mTOR pathwayTSC1Insulin receptorCell biologyRHEBTSC2InsulinPhosphorylationSignal transductionPhosphoinositide 3-kinaseEffectorCancer researchKinaseIRS1Insulin receptor substratemTORC1EndocrinologyInsulin resistance

MeSH Terms

AnimalsCell SurvivalChemotaxisFibroblastsInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsMicePhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationProteinsRepressor ProteinsRibosomal Protein S6 KinasesSignal TransductionTuberous Sclerosis Complex 1 ProteinTuberous Sclerosis Complex 2 ProteinTumor Suppressor Proteins

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Publication Info

Year: 2004
Type: article
Volume: 166
Issue: 2
Pages: 213-223
Citations: 1103
Access: Closed

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APA Style

                            
                                
                                    Laura Harrington, 
                                
                                    Greg M. Findlay, 
                                
                                    Alexander Gray
                                
                                et al.
                            
                            (2004). 
                            The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins. 
                            The Journal of Cell Biology
                            , 166
                            (2)
                            , 213-223.
                            https://doi.org/10.1083/jcb.200403069
                        

Identifiers

DOI: 10.1083/jcb.200403069
PMID: 15249583
PMCID: PMC2172316

Data Quality

Data completeness: 86%