A model of activation of the protein tyrosine phosphatase SHP-2 by the human leptin receptor

Löthgren, Agneta; McCartney, Mark; Thuresson, Eva Rupp; James, Sarah

doi:10.1016/s0167-4838(00)00257-0

Cited by 8 publications

(4 citation statements)

References 17 publications

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“…Activation of Tyr 985 is required for triggering rat sarcoma (Ras)/rapidly accelerated fibrosarcoma (Raf)/extracellular signal-regulated kinases 1/2 (ERK1/2) pathways through interaction with an adaptor protein, growth factor receptor-bound protein 2 (GRB2) [ 47 ]. Phosphorylation at Tyr 986 (Tyr 985 in rodents) and Tyr 974 leads to SH2 domain-containing tyrosine phosphatase 2 (SHP2), also called protein tyrosine phosphatase, non-receptor type 11 (PTPN11) binding to these residues [ 48 ]. While binding of SHP2 to Tyr 986 leads to its activation it has been proposed that this is followed by SHP2-mediated dephosphorylation of Tyr 974, suggesting the ability of SHP2 to down-regulate activity of proteins binding at this site [ 48 ].…”

Section: Leptin Signalling and Its Physiological Rolementioning

confidence: 99%

“…Phosphorylation at Tyr 986 (Tyr 985 in rodents) and Tyr 974 leads to SH2 domain-containing tyrosine phosphatase 2 (SHP2), also called protein tyrosine phosphatase, non-receptor type 11 (PTPN11) binding to these residues [ 48 ]. While binding of SHP2 to Tyr 986 leads to its activation it has been proposed that this is followed by SHP2-mediated dephosphorylation of Tyr 974, suggesting the ability of SHP2 to down-regulate activity of proteins binding at this site [ 48 ]. LEPR lacking Tyr 985 induces activation of ERK, although at a reduced rate, and this is due to an alternative ERK1/2 activation pathway, independent of receptor phosphorylation, via interaction of SHP2 and GRB2 with JAK2 [ 49 ].…”

Section: Leptin Signalling and Its Physiological Rolementioning

confidence: 99%

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Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

et al. 2015

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The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited.Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive.Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.

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Section: Leptin Signalling and Its Physiological Rolementioning

confidence: 99%

Section: Leptin Signalling and Its Physiological Rolementioning

confidence: 99%

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

et al. 2015

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“…The src-homology-2 domain containing protein tyrosine phosphatase 2 (SHP-2) has recently been shown to modulate leptin signal transduction by reducing tyrosine pY of both JAK-2 and IRS-1 (49)(50)(51)(52)(53), an observation that could be relevant to the downregulation of IRS tyrosine pY observed at high leptin concentrations. High leptin induced up-regulation of SHP-2 (53).…”

Section: Leptin and Insulin Signal Transductionmentioning

confidence: 99%

Short-Term Leptin-Dependent Inhibition of Hepatic Gluconeogenesis Is Mediated by Insulin Receptor Substrate-2

Anderwald

Müller²,

Koca

et al. 2002

Molecular Endocrinology

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Leptin has both insulin-like and insulin-antagonistic effects on glucose metabolism. To test whether leptin interferes directly with insulin signaling, we perfused isolated rat livers with leptin (0.1, 0.5, 5, and 25 nmol/liter), leptin + insulin (5 nmol/liter + 10 nmol/liter), insulin (10 nmol/liter), or vehicle (control). Leptin reduced L-lactate-(10 mmol/liter)-stimulated glucose production by 39-66% (P < 0.006 vs. control) and phosphoenolpyruvate carboxykinase (PEPCK) activity by 22-52% (P < 0.001). Physiological leptin concentrations (0.1-5 nmol/liter) stimulated the tyrosine phosphorylation (pY) of insulin receptor substrate-2 (IRS-2) (280-954%; P < 0.05) and its associated phosphatidylinositol-3 kinase activity (122-621%; P < 0.003). Leptin (0.5-25 nmol/liter) inhibited IRS-1 pY and its associated phosphatidylinositol-3 kinase activity (20-89%; P < 0.03) but stimulated janus kinase-2 pY (272-342%; P < 0.001). Leptin also down-regulated its short receptor isoform in a time- and concentration-dependent manner (28-54%; P < 0.05). Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (approximately 50%; P < 0.001 vs. control) and doubled IRS-2 pY (P < 0.01 vs. insulin). However, leptin + insulin decreased IRS-1 pY by 57% (P < 0.01 vs. insulin). Insulin alone (P < 0.01), but not leptin, increased autophosphorylation of nonreceptor tyrosine kinases (pp59(Lyn) + pp125(Fak)). In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway.

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“…Enzyme was stored in a buffer consisting of 25 mM Tris-HCl, pH 7.5, 300 mM NaCl, 1 mM EDTA, and 3 mM DTT at Ϫ70°C. A glutathione S-transferase fusion protein containing the active site of SHP-2 was expressed and purified as described previously (Löthgren et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

Oxidation of Protein Tyrosine Phosphatases as a Pharmaceutical Mechanism of Action: A Study Using 4-Hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione

Liljebris¹,

Baranczewski²,

Björkstrand³

et al. 2004

J Pharmacol Exp Ther

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A model of activation of the protein tyrosine phosphatase SHP-2 by the human leptin receptor

Cited by 8 publications

References 17 publications

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

Short-Term Leptin-Dependent Inhibition of Hepatic Gluconeogenesis Is Mediated by Insulin Receptor Substrate-2

Oxidation of Protein Tyrosine Phosphatases as a Pharmaceutical Mechanism of Action: A Study Using 4-Hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione

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