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. Author manuscript; available in PMC: 2016 Sep 28.
Published in final edited form as: Expert Rev Gastroenterol Hepatol. 2015 Sep 28;9(11):1407–1419. doi: 10.1586/17474124.2015.1092383

Figure 2.

Figure 2

Schematic representation of the mammalian target of rapamycin (mTOR) signaling pathway and crosstalk with the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway. The mTOR protein is present in two different complexes (mTORC1 and mTORC2) that are activated through two different signaling cascades. MTORC1 is the principal target of rapamycin analogs (rapalogs), including everolimus, while mTORC2 seems not to be sensitive to these agents. Inhibition of mTORC1 by everolimus might cause a lack of inactivation of IRS-1, resulting in an upregulation by feedback loop mechanisms of the PI3K and MAPK pathways. This seems to be one of the main mechanisms that leads to the development of resistance against mTOR inhibitors. (#) Genes with germline mutations characterizing inherited syndromes with predisposition to PanNETs. (*) Genes with somatic mutations found in sporadic PanNETs. Other abbreviations: 4E-BP1, eIF4E-binding protein 1;EGFR, epidermal growth factor receptor; ERK, extracellular signal–regulated kinase; IGFR, insulin- like growth factor receptor; IRS1, insulin receptor substrate 1; MEK, MAP–ERK kinase; PIP2, phosphatidylinositol (4,5)-biphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PTEN, phosphatase and tensin homolog deleted at chromosome; S6K1, p70 S6 kinase 1; TSC, tuberous sclerosis complex.