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

By L. Harrington, Greg M. Findlay, A. Gray, T. Tolkacheva, S. Wigfield, H. rebholz, Jill Barnett, Nick R. Leslie, Susan Cheng, P. R. Shepherd and 3 more. Journal of Cell Biology, 2004

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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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/eebd18bd5a7d8b2768de70e896d5e6ebe71d71e8

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Citations in the corpus

AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. (2005, neutral): “In addition, S6K1 activation decreases IRS protein levels through alterations in transcription and protein degradation (Harrington et al., 2004; Shah et al., 2004).”
TOR signaling in growth and metabolism. (2006, background): “Recent studies have highlighted the existence of a negative feedback loop from the nutrient-sensitive TSC-mTOR-S6K1 pathway to the upstream, insulin-responsive IRS-PI3K-PDK1Akt pathway (Figure 2; Harrington et al., 2004; Shah et al., 2004; Um et al., 2004).”
Ras, PI(3)K and mTOR signalling controls tumour cell growth (2006, background): “Subsequently, in both flies and mammals, TSC-deficient cells were found to have extremely low levels of AKT activation, even after growth-factor stimulation, despite high mTORC1 activit”
Rapamycin passes the torch: a new generation of mTOR inhibitors (2011, background): “mTORC1, via S6K phosphorylating insulin receptor substrate 1 (IRS1), can dampen upstream insulin signallin”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “65 The negative feedback loop among insulin-dependent PI3K pathway and mTORC1 is another mechanism for the mTOR2 regulation (Fig.”
The Lin28/let-7 axis regulates glucose metabolism (2011, background): “Conversely, TSC1-2 promotes insulin-PI3K signaling by suppressing mTOR signaling (Harrington et al., 2004; Shah et al., 2004).”
Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. (2005, background): “…processes through a wide variety of newly established substrates (de Groot et al. 1994; Wilson et al. 2000; Harada et al. 2001; Wang et al. 2001; Harrington et al. 2004; Raught et al. 2004; Richardson et al. 2004). rpS6 phosphorylation and protein synthesis Our present results have established…”
LKB1 and AMPK control of mTOR signalling and growth (2009, background): “…hyperlipidaemia and hyperinsulinaemia in the circulation is chronic hyperactivation of the mTORC1 complex, and that mTORC1 and its downstream effector S6K1 both directly phosphorylate the IRS family of scaffolds leading to their targeted degradation (Harrington et al. 2004, Shah et al. 2004).”
Dysregulation of the TSC-mTOR pathway in human disease (2004, background): “Several recent studies indicate that this negative feedback occurs by S6K-mediated downregulation of insulin receptor substrate activit”