The TOR Kinases Link Nutrient Sensing to Cell Growth

Rohde, John R.; Heitman, Joseph; Cárdenas, María E.

doi:10.1074/jbc.r000034200

Cited by 329 publications

(251 citation statements)

References 73 publications

Supporting

Mentioning

250

Contrasting

Order By: Relevance

“…A cellular nutrient sensor, mTOR, has been identified as a critical element integrating cellular metabolism with growth factor signaling (42)(43)(44)(45). In response to insulin and amino acids, mTOR, which is a serine/threonine kinase, phosphorylates and modulates activities of p70 S6 kinase (S6K1 kinase) and an inhibitor of translational initiation, eIF-4E binding protein (46 -48).…”

Section: Serine Phosphorylation Of Irs-1mentioning

confidence: 99%

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

2006

View full text Add to dashboard Cite

Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85␣ has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85␣ and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance. Diabetes 55: 2392-2397, 2006 E ven though insulin resistance has emerged as an enormous health care problem, trespassing the fields of obesity, diabetes, hypertension, and cardiovascular diseases (1,2), its molecular mechanism remains incompletely understood. Clinically, the term insulin resistance implies that higher-than-normal concentrations of insulin are required to maintain normoglycemia. On a cellular level, this term defines an inadequate strength of insulin signaling from the insulin receptor downstream to the final substrates of insulin action involved in multiple metabolic and mitogenic aspects of cellular function (3).Insulin action is initiated by an interaction of insulin with its cell surface receptor (4). The insulin receptor is a heterotetrameric protein that consists of two extracellular ␣ subunits and two transmembrane ␤ subunits connected by disulfide bridges (5-7). Insulin binding to the extracellular ␣ subunit induces conformational changes of the insulin receptor that activate the tyrosine kinase domain of the intracellular portion of the ␤ subunit (8 -11). Once the tyrosine kinase of insulin receptors is activated, it promotes autophosphorylation of the ␤ subunit itself, where phosphorylation of three tyrosine residues (Tyr-1158, Tyr-1162, and Tyr-1163) is required for amplification of the kinase activity (12,13). Activation of the tyrosine kinase of the insulin receptor also leads to a rapid phosphorylation of the so-called "docking proteins," such as insulin receptor substrate (IRS)-1, -2, -3, and -4, and several Shc proteins (52-, 46-, and...

show abstract

Section: Serine Phosphorylation Of Irs-1mentioning

confidence: 99%

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

2006

View full text Add to dashboard Cite

show abstract

“…The nutrient sensing function of TOR is evolutionarily conserved (reviewed in Rohde et al, 2001;Crespo and Hall, 2002). In S. cerevisiae, TOR is sensitive to changes in amino-acid, nitrogen, and glucose levels, and inhibition of TOR with rapamycin or by TOR deletion triggers a response program similar to nutrient starvation.…”

Section: Nutrient Sensing Of Amino-acid and Energy Signalsmentioning

confidence: 99%

“…TOR regulates, both positively and negatively, a diverse array of nutrient-regulated metabolic genes. TOR controls ribosome biogenesis by controlling the expression of ribosomal protein mRNAs as well as the transcription of rRNA and tRNA (reviewed in Rohde et al, 2001;Crespo and Hall, 2002). Gene expression is also regulated by TOR by controlling the subcellular localization of transcription factors; for example, TOR-dependent phosphorylation of the GATA transcription factor GLN3 allows it to bind to and be sequestered in the cytoplasm by the repressor URE2 (Beck and Hall, 1999).…”

Section: Tor-dependent Regulation Of Cellular Processes Other Than Trmentioning

confidence: 99%

“…While the role of mTOR in control of protein synthesis in mammals is well documented, analogies to TOR function in S. cerevisiae suggest that mTOR will be shown to play important roles in a diverse array of cellular processes in addition to protein synthesis (reviewed in Rohde et al, 2001;Crespo and Hall, 2002). Mutation of TOR in budding yeast or rapamycin treatment elicits changes in gene expression, amino-acid permease function, autophagy, and the organization of the actin cytoskeleton, as well as inhibition of protein synthesis.…”

Section: Tor-dependent Regulation Of Cellular Processes Other Than Trmentioning

confidence: 99%

See 1 more Smart Citation

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

View full text Add to dashboard Cite

Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

show abstract

“…A cellular nutrient sensor, mTOR, has been identified as a critical element integrating cellular metabolism with growth factor signalling [20][21][22][23]. In response to insulin and amino acids, mTOR phosphorylates and modulates the activities of p70 S6 kinase and an inhibitor of translational initiation, eIF-4E-binding protein [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis: We sought to define early molecular alterations associated with nutritionally induced insulin resistance in humans. Methods: Insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic clamp in eight healthy women while on an isocaloric diet and after 3 days of overfeeding (50% above eucaloric diet). Expression of phosphatidylinositol (PI) 3-kinase subunits p85α and p110 was assessed and measurements were made of IRS-1-associated PI 3-kinase activity, tyrosine and serine phosphorylation of IRS-1, and serine and threonine phosphorylation of p70S6 kinase. Measurements were made in skeletal muscle biopsies obtained before and after overfeeding. Results: Three days of overfeeding resulted in a reduction of insulin sensitivity accompanied by: (1) increased expression of skeletal muscle p85α; (2) an alteration in the ratio of p85α to p110; (3) a decrease in the amount of IRS-1-associated p110; and (4) a decrease in PI 3-kinase activity. Increases in expression of p85α and in the p85α:p110 ratio demonstrated a highly significant inverse correlation with insulin sensitivity, and changes in PI 3-kinase activity correlated with changes in insulin sensitivity. Tyrosine and serine phosphorylation of IRS-1 and serine and threonine phosphorylation of p70S6 kinase were unaffected by 3 days of overfeeding. Conclusions/interpretation: We identified a novel mechanism of nutritionally induced insulin resistance in healthy women of normal weight. We conclude that increased expression of p85α may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding.

show abstract

The TOR Kinases Link Nutrient Sensing to Cell Growth

Cited by 329 publications

References 73 publications

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

Contact Info

Product

Resources

About