Proline-rich Akt substrate of 40kDa (PRAS40): A novel downstream target of PI3k/Akt signaling pathway

Wang, Haitao; Qishan, Zhang; Wen, Qiang; Zheng, Yongxin; Lazarovici, Philip; Jiang, Hao; Lin, Jun; Zheng, Wenhua

doi:10.1016/j.cellsig.2011.08.010

Cited by 143 publications

(95 citation statements)

References 88 publications

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“…Rapa, rapamycin; PF, PF-4708671 Accordingly, overexpression of PRAS40 impaired the insulin-mediated phosphorylation of the mTORC1 substrates p70S6K and 4E-BP1 [19,20,22,23]. These findings led to the suggestion that the dissociation of phosphorylated PRAS40 from raptor could promote downstream mTORC1 signalling by increasing substrate binding to raptor [16,17]. However, this proposed function for PRAS40 is in contrast with our findings on hSkMC and multiple other studies [16,22,33,34].…”

Section: Discussioncontrasting

confidence: 56%

“…In PRAS40-KD hSkMC, this is illustrated by reduced phosphorylation of the p70S6K-Thr412, ribosomal protein S6-Ser240 and 4E-BP1-Thr37/Thr46 and, for the first time, also by a reduced level of GRB10, a newly identified mTORC1 substrate that has its levels stabilised through phosphorylation by mTORC1 [9][10][11]. Although genetic evidence obtained in D. melanogaster hints at a tissue-specific regulation of the drosophila TORC1 pathway by drosophila PRAS40 [24], the impaired activation of the mTORC1 signalling pathway by insulin in the present study most likely results from a reduced activation of the IRS1-Akt-TSC2 axis in PRAS40-KD myotubes, rather than from a direct role for PRAS40 in the regulation of mTORC1 signalling [16,17].…”

Section: Discussioncontrasting

confidence: 47%

“…Because some studies have hinted at an inhibitory role for PRAS40 within mTORC1 [16,17], we next evaluated whether the effects of PRAS40-KD could be ascribed to hyperactivation of the mTORC1 pathway. To monitor activation of the mTORC1 pathway, we first examined the phosphorylation of the mTORC1 substrates p70S6K and 4E-BP1.…”

Section: Resultsmentioning

confidence: 99%

“…The impaired activity of the IRS1/PI3K/Akt pathway also results in reduced insulinmediated phosphorylation of one of the most prominent Akt substrates, the proline-rich Akt substrate of 40 kDa (PRAS40), in skeletal muscle of humans with type 2 diabetes and rodents fed a high-fat diet [13][14][15]. PRAS40 is a component of mTORC1 [16,17]. Yet studies of the function of this protein within mTORC1 have yielded conflicting results [18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Wiza

Nascimento

et al. 2013

Diabetologia

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Aims/hypothesis The proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex 1 (mTORC1) and among the most prominent Akt substrates in skeletal muscle. Yet the cellular functions of PRAS40 are incompletely defined. This study assessed the function of PRAS40 in insulin action in primary human skeletal muscle cells (hSkMC). Methods Insulin action was examined in hSkMC following small interfering RNA-mediated silencing of PRAS40 (also known as AKT1S1) under normal conditions and following chemokine-induced insulin resistance. Results PRAS40 knockdown (PRAS40-KD) in hSkMC decreased insulin-mediated phosphorylation of Akt by 50% (p<0.05) as well as of the Akt substrates glycogen synthase kinase 3 (40%) and tuberous sclerosis complex 2 (32%) (both p<0.05). Furthermore, insulin-stimulated glucose uptake was reduced by 20% in PRAS40-KD myotubes (p<0.05). Exposing PRAS40-KD myotubes to chemokines caused no additional deterioration of insulin action. PRAS40-KD further reduced insulin-mediated phosphorylation of the mTORC1-regulated proteins p70S6 kinase (p70S6K) (47%), S6 (43%), and eukaryotic elongation 4E-binding protein 1 (100%), as well as protein levels of growth factor receptor bound protein 10 (35%) (all p<0.05). The inhibition of insulin action in PRAS40-KD myotubes was associated with a reduction in IRS1 protein levels (60%) (p<0.05), and was reversed by pharmacological proteasome inhibition. Accordingly, expression of the genes encoding E3-ligases Fbox protein 32 (also known as atrogin-1) and muscle RINGfinger protein-1 and activity of the proteasome was elevated in PRAS40-KD myotubes. Conclusions/interpretation Inhibition of insulin action in PRAS40-KD myotubes was found to associate with IRS1 degradation promoted by increased proteasome activity rather than hyperactivation of the p70S6K-negative-feedback loop. These findings identify PRAS40 as a modulator of insulin action.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussioncontrasting

confidence: 47%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Wiza

Nascimento

et al. 2013

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Other names Lobe PRAS40 HGNC (Hugo) AKT1S1 Location 19q13.33 Note Akt1 substrate 1 (AKT1S1), also known as prolinerich Akt substrate of 40-kDa (PRAS40) is a component of the Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling cascades (Nascimento and Ouwens, 2009;Wang et al, 2012;Wiza et al, 2012). AKT1S1 can act as a negative regulator of the mTORC1 complex, and binds YWHAZ (14-3-3) when phosphorylated (Nascimento and Ouwens, 2009;Wang et al, 2012;Wiza et al, 2012).…”

Section: Identitymentioning

confidence: 99%