PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR

Zhang, Hongbing; Bajraszewski, Natalia; Wu, Erxi; Wang, Hongwei; Moseman, Annie P.; Dabora, Sandra L.; Griffin, James D.; Kwiatkowski, David J.

doi:10.1172/jci28984

Cited by 332 publications

(322 citation statements)

References 49 publications

(17 reference statements)

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“…Rapamycin activated Akt and increased expression of the platelet-derived growth factor receptor in TSC-deficient cells (30). However, the mechanism does not appear to be inhibition of plateletderived growth factor receptor degradation as is the case for IRS-1, but an effect at the mRNA level.…”

Section: Discussionmentioning

confidence: 93%

Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling

Martin

Merenick

Ding

et al. 2007

Journal of Biological Chemistry

131

170

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The phenotypic plasticity of mature vascular smooth muscle cells (VSMCs) facilitates angiogenesis and wound healing, but VSCM dedifferentiation also contributes to vascular pathologies such as intimal hyperplasia. Insulin/insulin-like growth factor I (IGF-I) is unique among growth factors in promoting VSMC differentiation via preferential activation of phosphatidylinositol 3-kinase (PI3K) and Akt. We have previously reported that rapamycin promotes VSMC differentiation by inhibiting the mammalian target of rapamycin (mTOR) target S6K1. Here, we show that rapamycin activates Akt and induces contractile protein expression in human VSMC in an insulin-like growth factor I-dependent manner, by relieving S6K1-dependent negative regulation of insulin receptor substrate-1 (IRS-1). In skeletal muscle and adipocytes, rapamycin relieves mTOR/S6K1-dependent inhibitory phosphorylation of IRS-1, thus preventing IRS-1 degradation and enhancing PI3K activation. We report that this mechanism is functional in VSMCs and crucial for rapamycin-induced differentiation. Rapamycin inhibits S6K1-dependent IRS-1 serine phosphorylation, increases IRS-1 protein levels, and promotes association of tyrosine-phosphorylated IRS-1 with PI3K. A rapamycin-resistant S6K1 mutant prevents rapamycin-induced Akt activation and VSMC differentiation. Notably, we find that rapamycin selectively activates only the Akt2 isoform and that Akt2, but not Akt1, is sufficient to induce contractile protein expression. Akt2 is required for rapamycin-induced VSMC differentiation, whereas Akt1 appears to oppose contractile protein expression. The anti-restenotic effect of rapamycin in patients may be attributable to this unique pattern of PI3K effector regulation wherein anti-differentiation signals from S6K1 are inhibited, but pro-differentiation Akt2 activity is promoted through an IRS-1 feedback signaling mechanism. Vascular smooth muscle cells (VSMCs)3 maintain a phenotypic plasticity that is important in physiological processes such as arteriogenesis, and in pathological responses, including atherosclerosis, intimal hyperplasia, and restenosis. Mature VSMCs are quiescent and exhibit a differentiated, contractile phenotype. Differentiation status in vitro can be measured by expression of smooth muscle-specific contractile proteins, including calponin, caldesmon, and smooth muscle myosin heavy chain (SM-MHC) (1). In response to injury, or upon in vitro culture, VSMCs re-enter the cell cycle, proliferate, migrate toward attractants, down-regulate expression of contractile proteins, and up-regulate protein synthesis, particularly of the extracellular matrix. This de-differentiated phenotype is referred to as "synthetic" because of this property (1).VSMC de-differentiation and resultant intimal hyperplasia in response to vessel injury are common problems following vascular interventions such as angioplasty, stent placement, and bypass grafts. Since receiving FDA approval in 2003, the use of the mTOR inhibitor rapamycin on drug-eluting stents has had a profound impac...

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Section: Discussionmentioning

confidence: 93%

Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling

Martin

Merenick

Ding

et al. 2007

Journal of Biological Chemistry

131

170

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“…We have previously shown that feedback activation of Akt signaling significantly inhibits the clinical efficacy of rapamycin (10). This appears to be mediated through S6K1 inhibition and up-regulation of receptor tyrosine kinases or their substrates (11,15), although the factors that mediate feedback activation in patients have yet to be fully elucidated. Here we asked whether expression of the most common EGFR mutant, constitutively active, ligand-independent mutant EGFRvIII (16,17) could accentuate the feedback activation of Akt in response to rapamycin.…”

Section: Resultsmentioning

confidence: 99%

The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis

Guo¹,

Hildebrandt²,

Prins³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

224

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The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by 18 fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.

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“…BEX2 antibody was from Abcam (Cambridge, MA). Anti-phospho-S6 (Ser-235/236) and anti-S6 antibodies have been described previously (28), TSC2, ␤-actin, and all HRP-labeled secondary antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA). STAT3, p-STAT3 (Tyr-705), p65, p-p65 (Ser-536), mTOR, Raptor, Rictor, and PTEN antibodies were from Cell Signaling Technology (Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

Wang

Huang

et al. 2015

Journal of Biological Chemistry

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PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR

Cited by 332 publications

References 49 publications

Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling

Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling

The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis

Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

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