Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

Liu, J; Grieve, Sandra; Boudreau, Jeff R.; Yeung, Benjamin; Lo, Szecheng J.; Chamberlain, Gabriel; Yu, Fabian P. S.; Sun, Tiansong; Papanicolaou, Tony; Lam, A; Yang, Xiaolong; Chin-Sang, Ian D.

doi:10.1038/onc.2013.347

Cited by 29 publications

(19 citation statements)

References 47 publications

(60 reference statements)

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“…11a ). Protein levels of the PKB negative regulator PTEN are reduced by IR overexpression 42 , and in accordance we detected low PTEN levels in BACE1 −/− livers (Fig. 6e and Supplementary Fig.…”

Section: Resultssupporting

confidence: 86%

The beta secretase BACE1 regulates the expression of insulin receptor in the liver

et al. 2018

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Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.

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Section: Resultssupporting

confidence: 86%

The beta secretase BACE1 regulates the expression of insulin receptor in the liver

et al. 2018

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“…Both Ser/Thr and tyrosine phosphorylation are known to regulate PTEN phosphorylation (44). Two studies reported tyrosine phosphorylation of PTEN by key RTK signaling molecules (namely Eph and IR) at various tyrosine residues, which results in destabilization and further downregulation of PTEN (45)(46)(47). However, Yim et al (48) showed that Rak tyrosine signaling phosphorylates Y336 and stabilizes PTEN.…”

Section: Negative Association Of Grb10 With Ptenmentioning

confidence: 99%

Proproliferative function of adaptor protein GRB10 in prostate carcinoma

et al. 2018

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Growth factor receptor‐binding protein 10 (GRB10) is a well‐known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt‐targeted therapies in prostate cancer (PCa) is loss of mTOR‐regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)‐deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild‐type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild‐type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K‐driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor‐promoting effects in prostate cancer.—Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Proproliferatve function of adaptor protein GRB10 in prostate carcinoma. FASEB J. 33, 3198–3211 (2019). http://www.fasebj.org

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“…Moreover, insulin signaling was found to inhibit PTEN expression (Liu et al 2014), and insulin resistance has been linked to increased FASN expression (Menendez et al 2009), indicating that aberrant insulin signaling may underlie altered PTEN and FASN expression levels and activity in CRC. To evaluate whether Lun, Gen, and/or MET attenuate CSC frequency by opposing insulin action, we exposed HCT116 cells to an elevated level of insulin (2 lM, modeling hyperinsulinemia) and determined effects of added factors on colonosphere formation and on the CD133 ?…”

Section: Soy Bioactive Components Alter Hct116 Cell Viability Apoptomentioning

confidence: 99%

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

et al. 2015

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Colorectal cancer (CRC) is a disease whose genesis may include metabolic dysregulation. Cancer stem cells are attractive targets for therapeutic interventions since their aberrant expansion may underlie tumor initiation, progression, and recurrence. To investigate the actions of metabolic regulators on cancer stem cell-like cells (CSC) in CRC, we determined the effects of soybeanderived bioactive molecules and the anti-diabetes drug metformin (MET), alone and together, on the growth, survival, and frequency of CSC in human HCT116 cells. Effects of MET (60 lM) and soybean components genistein (Gen, 2 lM), lunasin (Lun, 2 lM), b-conglycinin (bcon, 3 lM), and glycinin (Gly, 3 lM) on HCT116 cell proliferation, apoptosis, and mRNA/protein expression and on the frequency of the CSC CD133 ? CD44 ? subpopulation by colonosphere assay and fluorescence-activated cell sorting/flow cytometry were evaluated. MET, Gen, and Lun, individually and together, inhibited HCT116 viability and colonosphere formation and, conversely, enhanced HCT116 apoptosis. Reductions in frequency of the CSC CD133 ? CD44 ? subpopulation with MET, Gen, and Lun were found to be associated with increased PTEN and reduced FASN expression. In cells under a hyperinsulinemic state mimicking metabolic dysregulation and without and with added PTEN-specific inhibitor SF1670, colonosphere formation and frequency of the CD133 ? CD44 ? subpopulation were decreased by MET, Lun and Gen, alone and when combined. Moreover, MET ? Lun ? Gen co-treatment increased the pro-apoptotic and CD133 ?-CD44 ? -inhibitory efficacy of 5-fluorouracil under hyperinsulinemic conditions. Results identify molecular networks shared by MET and bioavailable soy food components, which potentially may be harnessed to increase drug efficacy in diabetic and non-diabetic patients with CRC.

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Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

Cited by 29 publications

References 47 publications

The beta secretase BACE1 regulates the expression of insulin receptor in the liver

The beta secretase BACE1 regulates the expression of insulin receptor in the liver

Proproliferative function of adaptor protein GRB10 in prostate carcinoma

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

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