bims-pideca 2020-05-10 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2020‒05‒10
nineteen papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute

Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?
A genome-scale CRISPR screen identifies the ERBB and mTOR signalling networks as key determinants of response to PI3K inhibition in pancreatic cancer.
Sequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila.
IGF1R constitutive activation expands luminal progenitors and influences lineage differentiation during breast tumorigenesis.
Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells.
GPx3 dysregulation impacts adipose tissue insulin receptor expression and sensitivity.
Control of Adipocyte Thermogenesis and Lipogenesis through β3-Adrenergic and Thyroid Hormone Signal Integration.
Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome.
Preclinical activity of PI3K inhibitor Copanlisib in Gastrointestinal Stromal Tumor.
Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells.
A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion.
Exploring the controversial role of PI3K signalling in CD4+ regulatory T (T-Reg) cells.
Insulin-stimulated lipogenesis gets an epigenetic makeover.
Hepatic Slug epigenetically promotes liver lipogenesis, fatty liver disease, and type 2 diabetes.
p85β regulates autophagic degradation of AXL to activate oncogenic signaling.
Enhanced insulin receptor interaction by a bifunctional insulin-transferrin fusion protein: an approach to overcome insulin resistance.
Contraction-regulated mTORC1 and protein synthesis - influence of AMPK and glycogen.
Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands.
Metabolic Regulation of Tissue Stem Cells.

Biochim Biophys Acta Mol Cell Res. 2020 Apr 29. pii: S0167-4889(20)30089-6. [Epub ahead of print] 118731

Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?

Luca Braglia, Manuela Zavatti, Marco Vinceti, Alberto M Martelli, Sandra Marmiroli.

  Although the prognosis of patients with localized prostate cancer is good after surgery, with a favorable response to androgen deprivation therapy, about one third of them invariably relapse, and progress to castration-resistant prostate cancer. Overall, prostate cancer therapies remain scarcely effective, thus it is mandatory to devise alternative treatments enhancing the efficacy of surgical castration and hormone administration. Dysregulation of the phosphoinositide 3-kinase pathway has attracted growing attention in prostate cancer due to the highly frequent association of epigenetic and post-translational modifications as well as to genetic alterations of both phosphoinositide 3-kinase and PTEN to onset and/or progression of this malignancy, and to resistance to canonical androgen-deprivation therapy. Here we provide a summary of the biological functions of the major players of this cascade and their deregulation in prostate cancer, summarizing the results of preclinical and clinical studies with PI3K signaling inhibitors and the reasons of failure independent from genomic changes.

Keywords:  PIK3CA mutation; PTEN deletion; PTEN/PI3K/AKT/mTOR signaling; Prostate cancer; Resistance; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbamcr.2020.118731
Mol Cancer Ther. 2020 May 05. pii: molcanther.1131.2019. [Epub ahead of print]

A genome-scale CRISPR screen identifies the ERBB and mTOR signalling networks as key determinants of response to PI3K inhibition in pancreatic cancer.

Charlotte K Milton, Annette J Self, Paul A Clarke, Udai Banerji, Federica Piccioni, David E Root, Steven R Whittaker.

KRAS-mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergise with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB-family receptor tyrosine kinase signalling and mTOR signalling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB-family or mTOR was synergistic with PI3K inhibition in spheroid, stromal co-cultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB-PI3K signalling axis were associated with decreased survival of pancreatic cancer patients. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signalling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.

DOI: https://doi.org/10.1158/1535-7163.MCT-19-1131
Nat Commun. 2020 May 08. 11(1): 2300

Sequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila.

Amandine Rambur, Corinne Lours-Calet, Claude Beaudoin, Julio Buñay, Marine Vialat, Vincent Mirouse, Amalia Trousson, Yoan Renaud, Jean-Marc A Lobaccaro, Silvère Baron, Laurent Morel, Cyrille de Joussineau.

One of the most important but less understood step of epithelial tumourigenesis occurs when cells acquire the ability to leave their epithelial compartment. This phenomenon, described as basal epithelial cell extrusion (basal extrusion), represents the first step of tumour invasion. However, due to lack of adequate in vivo model, implication of emblematic signalling pathways such as Ras/Mitogen-Activated Protein Kinase (MAPK) and phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathways, is scarcely described in this phenomenon. We have developed a unique model of basal extrusion in the Drosophila accessory gland. There, we demonstrate that both Ras/MAPK and PI3K/AKT/mTOR pathways are necessary for basal extrusion. Furthermore, as in prostate cancer, we show that these pathways are co-activated. This occurs through set up of Epidermal Growth Factor Receptor (EGFR) and Insulin Receptor (InR) dependent autocrine loops, a phenomenon that, considering human data, could be relevant for prostate cancer.

DOI: https://doi.org/10.1038/s41467-020-16123-w
Dev Biol. 2020 May 03. pii: S0012-1606(20)30127-5. [Epub ahead of print]

IGF1R constitutive activation expands luminal progenitors and influences lineage differentiation during breast tumorigenesis.

Susan M Farabaugh, Beate C Litzenburger, Ashuvinee Elangovan, Geoffrey Pecar, Lauren Walheim, Jennifer M Atkinson, Adrian V Lee.

  Breast tumors display tremendous heterogeneity in part due to varying molecular alterations, divergent cells of origin, and differentiation. Understanding where and how this heterogeneity develops is likely important for effective breast cancers eradication. Insulin-like growth factor (IGF) signaling is critical for normal mammary gland development and function, and has an established role in tumor development and resistance to therapy. Here we demonstrate that constitutive activation of the IGF1 receptor (IGF1R) influences lineage differentiation during mammary tumorigenesis. Transgenic IGF1R constitutive activation promotes tumors with mixed histologies, multiple cell lineages and an expanded bi-progenitor population. In these tumors, IGF1R expands the luminal-progenitor population while influencing myoepithelial differentiation. Mammary gland transplantation with IGF1R-infected mammary epithelial cells (MECs) resulted in hyperplastic, highly differentiated outgrowths and attenuated reconstitution. Restricting IGF1R constitutive activation to luminal versus myoepithelial lineage-sorted MECs resulted in ductal reconstitutions co-expressing high IGF1R levels in the opposite lineage of origin. Using in vitro models, IGF1R constitutively activated MCF10A cells showed increased mammosphere formation and CD44+/CD24-population, which was dependent upon Snail and NFκB signaling. These results suggest that IGF1R expands luminal progenitor populations while also stimulating myoepithelial cell differentiation. This ability to influence lineage differentiation may promote heterogeneous mammary tumors, and have implications for clinical treatment.

Keywords:  Breast cancer; Differentiation; IGF1R; Lineages

DOI:  https://doi.org/10.1016/j.ydbio.2020.04.007
Sci Rep. 2020 May 07. 10(1): 7714

Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells.

Fengsen Duan, Chunlei Mei, Luhao Yang, Junyan Zheng, Huiai Lu, Yanzhi Xia, Stacy Hsu, Huageng Liang, Ling Hong.

Vitamin K2 has been shown to exert remarkable anticancer activity. However, the detailed mechanism remains unclear. Here, our study was the first to show that Vitamin K2 significantly promoted the glycolysis in bladder cancer cells by upregulating glucose consumption and lactate production, whereas inhibited TCA cycle by reducing the amounts of Acetyl-CoA. Moreover, suppression of PI3K/AKT and HIF-1α attenuated Vitamin K2-increased glucose consumption and lactate generation, indicating that Vitamin K2 promotes PI3K/AKT and HIF-1α-mediated glycolysis in bladder cancer cells. Importantly, upon glucose limitation, Vitamin K2-upregulated glycolysis markedly induced metabolic stress, along with AMPK activation and mTORC1 pathway suppression, which subsequently triggered AMPK-dependent autophagic cell death. Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death. Furthermore, both inhibition of PI3K/AKT/HIF-1α and attenuation of glycolysis significantly blocked Vitamin K2-induced AMPK activation and subsequently prevented autophagic cell death. Collectively, these findings reveal that Vitamin K2 could induce metabolic stress and trigger AMPK-dependent autophagic cell death in bladder cancer cells by PI3K/AKT/HIF-1α-mediated glycolysis promotion.

DOI: https://doi.org/10.1038/s41598-020-64880-x
JCI Insight. 2020 May 05. pii: 136283. [Epub ahead of print]

GPx3 dysregulation impacts adipose tissue insulin receptor expression and sensitivity.

Robert Hauffe, Vanessa Stein, Chantal Chudoba, Tanina Flore, Michaela Rath, Katrin Ritter, Mareike Schell, Kristina Wardelmann, Stefanie Deubel, Johannes F Kopp, Maria Schwarz, Kai Kappert, Matthias Blüher, Tanja Schwerdtle, Anna P Kipp, Andre Kleinridders.

  Insulin receptor signaling is crucial for white adipose tissue (WAT) function. Consequently, lack of insulin receptor (IR) in WAT results in a diabetes-like phenotype. Yet, causes for IR downregulation in WAT of diabetic patients are not well understood. By using multiple mouse models of obesity and insulin resistance, we identify a common downregulation of the IR with a reduction of mRNA expression of the selenoproteins Txnrd3, Sephs2, and Gpx3. Consistently, GPX3 is also decreased in adipose tissue of insulin resistant and obese patients. Inducing Gpx3 expression via selenite treatment enhances IR expression via activation of the transcription factor Sp1 in 3T3-L1 preadipocytes and improves adipocyte differentiation and function. Feeding mice a selenium-enriched high-fat diet alleviates diet-induced insulin resistance with increased insulin sensitivity, decreased tissue inflammation and elevated IR expression in WAT. Again, IR expression correlates positively with Gpx3 expression, a phenotype which is also conserved in humans. Consequently, decreasing GPx3 using siRNA technique reduces IR expression in 3T3-L1 preadipocytes and insulin sensitivity. Overall our data identify GPx3 as a novel regulator of IR expression and insulin sensitivity in adipose tissue.

Keywords:  Adipose tissue; Endocrinology; Insulin signaling; Metabolism; Obesity

DOI:  https://doi.org/10.1172/jci.insight.136283
Cell Rep. 2020 May 05. pii: S2211-1247(20)30547-7. [Epub ahead of print]31(5): 107598

Control of Adipocyte Thermogenesis and Lipogenesis through β3-Adrenergic and Thyroid Hormone Signal Integration.

Adilson Guilherme, Batuhan Yenilmez, Alexander H Bedard, Felipe Henriques, Dianxin Liu, Alexandra Lee, Lauren Goldstein, Mark Kelly, Sarah M Nicoloro, Min Chen, Lee Weinstein, Sheila Collins, Michael P Czech.

  Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.

Keywords:  Adrb3; Gs-alpha; beige adipocytes; cAMP; de novo lipogenesis; mTORC1; sympathetic nerve; thyroid hormones

DOI:  https://doi.org/10.1016/j.celrep.2020.107598
Proc Natl Acad Sci U S A. 2020 May 07. pii: 202000118. [Epub ahead of print]

Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome.

Zhao Zhang, Thomas Gallagher, Philipp E Scherer, Bruce Beutler.

  Loss of KBTBD2 in all tissues causes the teeny phenotype, characterized by insulin resistance with late failure of insulin production, severe hyperglycemia/diabetes, lipodystrophy, hepatosteatosis, and growth retardation. KBTBD2 maintains insulin sensitivity in adipocytes by restricting the abundance of p85α. However, the possible physiological contribution or contributions of KBTBD2 have not yet been examined in other tissues. Here we show that mice with an adipocyte-specific knockout of Kbtbd2 accumulate p85α in white and brown adipose tissues, causing insulin resistance, moderate rather than severe hyperglycemia, sustained hyperinsulinemia without late failure of insulin production, and lipodystrophy leading to ectopic lipid accumulation in the liver. Adipocyte-extrinsic insulin resistance was observed in liver and muscle. None of these abnormalities were observed in liver- or muscle-specific Kbtbd2 knockout mice. Mice with Kbtbd2 knockout in adipocytes, liver, and muscle all showed normal growth, suggesting that KBTBD2 may be necessary to ensure IGF1 signaling in other tissues, notably bone. While much of the teeny phenotype results from loss of KBTBD2 in adipocytes, some features are adipocyte-extrinsic.

Keywords:  KBTBD2; adipocytes; diabetes; insulin resistance; p85a

DOI:  https://doi.org/10.1073/pnas.2000118117
Mol Cancer Ther. 2020 May 05. pii: molcanther.1069.2019. [Epub ahead of print]

Preclinical activity of PI3K inhibitor Copanlisib in Gastrointestinal Stromal Tumor.

Alfonso García-Valverde, Jordi Rosell, Garazi Serna, Claudia Valverde, Joan Carles, Paolo Nuciforo, Jonathan A Fletcher, Joaquin Arribas, Oliver Politz, César Serrano.

KIT or PDGFRA gain-of-function mutations are the primary drivers of gastrointestinal stromal tumor (GIST) growth and progression throughout the disease course. The PI3K/mTOR pathway is critically involved in the transduction of KIT/PDGFRA oncogenic signaling regardless of the type of primary and secondary mutations, and therefore emerges as a relevant targetable node in GIST biology. We evaluated in GIST preclinical models the anti-tumor activity of copanlisib, a novel pan-class-I PI3K inhibitor with predominant activity against p110α and p110δ isoforms, as single-agent and in combination with first-line KIT inhibitor imatinib. In vitro studies undertaken in one imatinib-sensitive (GIST-T1) and two imatinib-resistant (GIST-T1/670, GIST430/654) GIST cell models showed that single-agent copanlisib effectively suppressed PI3K pathway activation leading to decreased cell viability and proliferation in both imatinib-sensitive and -resistant cells irrespective of the type of primary or secondary KIT mutations. Simultaneous PI3K and KIT inhibition with copanlisib and imatinib resulted in enhanced impairment of cell viability in both imatinib-sensitive and -resistant GIST cell models, although apoptosis was mostly triggered in GIST-T1. Single-agent copanlisib inhibited GIST growth in vivo, and conjoined inhibition of PI3K and KIT was the most active therapeutic intervention in imatinib-sensitive GIST-T1 xenografts. Immunohistochemistry stain for cleaved-caspase 3 and phospho-S6 support a predominant antiproliferative effect of copanlisib in GIST. In conclusion, copanlisib has single-agent anti-tumor activity in GIST regardless KIT mutational status or sensitivity to imatinib. Effective KIT inhibition is necessary in order to achieve synergistic or additive effects with the combination of imatinib and any given PI3K/mTOR pathway inhibition.

DOI: https://doi.org/10.1158/1535-7163.MCT-19-1069
Cell Rep. 2020 May 05. pii: S2211-1247(20)30562-3. [Epub ahead of print]31(5): 107613

Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells.

Fernando Erra Díaz, Valeria Ochoa, Antonela Merlotti, Ezequiel Dantas, Ignacio Mazzitelli, Virginia Gonzalez Polo, Juan Sabatté, Sebastián Amigorena, Elodie Segura, Jorge Geffner.

  During inflammation, recruited monocytes can differentiate either into macrophages or dendritic cells (DCs); however, little is known about the environmental factors that determine this cell fate decision. Low extracellular pH is a hallmark of a variety of inflammatory processes and solid tumors. Here, we report that low pH dramatically promotes the differentiation of monocytes into DCs (monocyte-derived DCs [mo-DCs]). This process is associated with a reduction in glucose consumption and lactate production, the upregulation of mitochondrial respiratory chain genes, and the inhibition of mTORC1 activity. Interestingly, we also find that both serum starvation and pharmacological inhibition of mTORC1 markedly promote the differentiation of mo-DCs. Our study contributes to better understanding the mechanisms that govern the differentiation of monocytes into DCs and reveals the role of both extracellular pH and mTORC1 as master regulators of monocyte cell fate.

Keywords:  Monocytes; acidosis; dendritic cells; differentiation; inflammation; low pH; mTOR; metabolism; starvation

DOI:  https://doi.org/10.1016/j.celrep.2020.107613
Cell Metab. 2020 Apr 23. pii: S1550-4131(20)30186-8. [Epub ahead of print]

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion.

Aharon Helman, Andrew L Cangelosi, Jeffrey C Davis, Quan Pham, Arielle Rothman, Aubrey L Faust, Juerg R Straubhaar, David M Sabatini, Douglas A Melton.

  A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system of the neonate. Despite their central role in metabolic homeostasis, little is known about how pancreatic β cells adjust to the new nutritional challenge. Here, we find that after birth β cell function shifts from amino acid- to glucose-stimulated insulin secretion in correlation with the change in the nutritional environment. This adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway, which leads to intermittent mTORC1 activity. Disrupting nutrient sensitivity of mTORC1 in mature β cells reverts insulin secretion to a functionally immature state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived β cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrients regulate β cell function, thereby enabling a metabolic adaptation for the newborn.

Keywords:  embryo; in vitro differentiation; insulin secretion; mTORC1; maturation; nutrient sensing; pancreas; stem cell-derived β cells; β cells

DOI:  https://doi.org/10.1016/j.cmet.2020.04.004
Adv Biol Regul. 2020 Apr 23. pii: S2212-4926(20)30033-6. [Epub ahead of print] 100722

Exploring the controversial role of PI3K signalling in CD4+ regulatory T (T-Reg) cells.

Alessandro Poli, Roberta Fiume, Sara Mongiorgi, Antonio Zaurito, Bhavwanti Sheth, Magdalena Castellano Vidalle, Shidqiyyah Abdul Hamid, ScottT Kimber, Francesca Campagnoli, Stefano Ratti, Isabella Rusciano, Irene Faenza, Lucia Manzoli, Nullin Divecha.

  The immune system is a complex network that acts to protect vertebrates from foreign microorganisms and carries out immunosurveillance to combat cancer. In order to avoid hyper-activation of the immune system leading to collateral damage tissues and organs and to prevent self-attack, the network has the intrinsic control mechanisms that negatively regulate immune responses. Central to this negative regulation are regulatory T (T-Reg) cells, which through cytokine secretion and cell interaction limit uncontrolled clonal expansion and functions of activated immune cells. Given that positive or negative manipulation of T-Regs activity could be utilised to therapeutically treat host versus graft rejection or cancer respectively, understanding how signaling pathways impact on T-Regs function should reveal potential targets with which to intervene. The phosphatidylinositol-3-kinase (PI3K) pathway controls a vast array of cellular processes and is critical in T cell activation. Here we focus on phosphoinositide 3-kinases (PI3Ks) and their ability to regulate T-Regs cell differentiation and function.

Keywords:  FOXOP3; Immune system; Lipid kinase; Naive T reg; PI3K; Phosphoinositide

DOI:  https://doi.org/10.1016/j.jbior.2020.100722
J Clin Invest. 2020 May 04. pii: 137050. [Epub ahead of print]

Insulin-stimulated lipogenesis gets an epigenetic makeover.

Clarence R Manuel, Rebecca A Haeusler.

Hepatic de novo lipogenesis is a major contributor to nonalcoholic fatty liver disease (NAFLD). In this issue of the JCI, Liu and Lin et al. identified Slug as an epigenetic regulator of lipogenesis. Their findings suggest that Slug is stabilized by insulin signaling, and that it promotes lipogenesis by recruiting the histone demethylase Lsd1 to the fatty acid synthase gene promoter. On the other hand, genetic deletion or acute depletion of Slug, or Lsd1 inhibition, reduced lipogenesis and protected against obesity-associated NAFLD and insulin resistance in mice. This study advances our understanding of how lipogenesis is regulated downstream of insulin signaling in health and disease.

DOI: https://doi.org/10.1172/JCI137050
J Clin Invest. 2020 May 04. pii: 128073. [Epub ahead of print]

Hepatic Slug epigenetically promotes liver lipogenesis, fatty liver disease, and type 2 diabetes.

Yan Liu, Haiyan Lin, Lin Jiang, Qingsen Shang, Lei Yin, Jiandie D Lin, Wen-Shu Wu, Liangyou Rui.

  De novo lipogenesis is tightly regulated by insulin and nutritional signals to maintain metabolic homeostasis. Excessive lipogenesis induces lipotoxicity, leading to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Genetic lipogenic programs have been extensively investigated, but epigenetic regulation of lipogenesis is poorly understood. Here, we identified Slug as an important epigenetic regulator of lipogenesis. Hepatic Slug levels were markedly upregulated in mice by either feeding or insulin treatment. In primary hepatocytes, insulin stimulation increased Slug expression, stability, and interactions with epigenetic enzyme lysine-specific demethylase-1 (Lsd1). Slug bound to the fatty acid synthase (Fasn) promoter where Slug-associated Lsd1 catalyzed H3K9 demethylation, thereby stimulating Fasn expression and lipogenesis. Ablation of Slug blunted insulin-stimulated lipogenesis. Conversely, overexpression of Slug, but not a Lsd1 binding-defective Slug mutant, stimulated Fasn expression and lipogenesis. Lsd1 inhibitor treatment also blocked Slug-stimulated lipogenesis. Remarkably, hepatocyte-specific deletion of Slug inhibited the hepatic lipogenic program and protected against obesity-associated NAFLD, insulin resistance, and glucose intolerance in mice. Conversely, liver-restricted overexpression of Slug, but not the Lsd1 binding-defective Slug mutant, had the opposite effects. These results unveil an insulin/Slug/Lsd1/H3K9 demethylation lipogenic pathway that promotes NAFLD and type 2 diabetes.

Keywords:  Diabetes; Hepatology; Insulin; Insulin signaling; Metabolism

DOI:  https://doi.org/10.1172/JCI128073
Nat Commun. 2020 May 08. 11(1): 2291

p85β regulates autophagic degradation of AXL to activate oncogenic signaling.

Ling Rao, Victor C Y Mak, Yuan Zhou, Dong Zhang, Xinran Li, Chloe C Y Fung, Rakesh Sharma, Chao Gu, Yiling Lu, George L Tipoe, Annie N Y Cheung, Gordon B Mills, Lydia W T Cheung.

PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.

DOI: https://doi.org/10.1038/s41467-020-16061-7
Sci Rep. 2020 May 07. 10(1): 7724

Enhanced insulin receptor interaction by a bifunctional insulin-transferrin fusion protein: an approach to overcome insulin resistance.

Yuqian Liu, Hsuan-Yao Wang, Juntang Shao, Jennica L Zaro, Wei-Chiang Shen.

Bifunctional fusion protein design has been widely utilized as a strategy to increase the efficacy of protein therapeutics. Previously, we proposed a novel application of the bifunctional fusion protein design through the introduction of proinsulin-transferrin (ProINS-Tf) fusion protein as a liver-specific protein prodrug to achieve a glucose-lowering effect in type 1 diabetic mice. In this report, we studied the binding characteristics of this activated fusion protein to the insulin receptor to elucidate its mechanism in eliciting insulin receptor-mediated signaling. We found that, with the assistance of the transferrin moiety binding to the transferrin receptor, the activated ProINS-Tf exhibited significantly higher binding affinity to the insulin receptor compared with the native insulin, resulting in a prolonged and stronger Akt phosphorylation. This enhanced induction by activated ProINS-Tf overcame insulin resistance in palmitate-treated HepG2 cells. ProINS-Tf also demonstrated a better glucose-lowering effect than native insulin, even with a much lower dose and less frequent injections, in non-obese diabetic mice with insulin resistance symptoms. The activated ProINS-Tf, serving as a bivalent protein molecule, could be a new insulin analog to overcome insulin resistance, which is associated with several diseases, including type 2 diabetes and non-alcoholic fatty liver disease.

DOI: https://doi.org/10.1038/s41598-020-64731-9
J Physiol. 2020 May 05.

Contraction-regulated mTORC1 and protein synthesis - influence of AMPK and glycogen.

Jonas R Knudsen, Zhencheng Li, Kaspar W Persson, Jingwen Li, Carlos Henriquez-Olguin, Thomas E Jensen.

HIGHLIGHTS: AMPK-dependent Raptor Ser792 phosphorylation does not influence mTORC1-S6K1 activation by intense muscle contraction. α2 -AMPK activity-deficient mice have lower contraction-stimulated protein synthesis Increasing glycogen activates mTORC1-S6K1 independently of AMPK α2 Normalizing muscle glycogen content rescues reduced protein synthesis in AMPK-deficient mice ABSTRACT: Objective The mammalian Target of Rapamycin Complex 1 (mTORC1)-S6K1 signalling pathway regulates muscle growth-related protein synthesis and is antagonized by AMP-activated protein kinase (AMPK) in multiple cell types. Resistance exercise stimulates skeletal muscle mTORC1-S6K1 and AMPK signalling and post-contraction protein synthesis. Glycogen inhibits AMPK and has been proposed as a pro-anabolic stimulus. The aim of this study was to investigate how muscle mTORC1-S6K1 signalling and protein synthesis respond to resistance exercise-mimicking contraction in the absence of AMPK and with glycogen-manipulation. Methods Resistance exercise-mimicking unilateral in situ contraction of m. quadriceps femoris on anaesthetized wild-type and dominant negative α2 AMPK kinase dead transgenic (KD-AMPK) mice, measuring muscle mTORC1 and AMPK signalling immediately (0h) and 4h post-contraction, and protein-synthesis at 4h. Muscle glycogen manipulation by 5-day oral gavage of the glycogen phosphorylase inhibitor CP316819 and sucrose (80 g L-1 ) in the drinking water prior to in situ contraction. Results The mTORC1-S6K1 and AMPK signalling axes were co-activated immediately post-contraction, despite potent AMPK-dependent Raptor Ser792 phosphorylation on the mTORC1 subunit Raptor. KD-AMPK muscles displayed normal mTORC1-S6K1 activation at 0h and 4h post-exercise, but impaired contraction-stimulated protein synthesis 4h post-contraction. Pharmacological/dietary elevation of muscle glycogen content augmented contraction-stimulated mTORC1-S6K1-S6 signalling and rescued the reduced protein synthesis-response in KD-AMPK to WT levels. Conclusions mTORC-S6K1 signalling is not influenced by α2 -AMPK during or after intense muscle contraction. Elevated glycogen augments mTORC1-S6K1 signalling. α2 -AMPK-deficient KD-AMPK mice display impaired contraction-induced muscle protein synthesis, which can be rescued by normalizing muscle glycogen content. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1113/JP279780
Front Physiol. 2020 ;11 354

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands.

Meng Zhao, Yunshin Jung, Zewen Jiang, Katrin J Svensson.

  Metabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.

Keywords:  glucose; lipids; metabolism; receptor tyrosine kinases; signaling

DOI:  https://doi.org/10.3389/fphys.2020.00354
Trends Cell Biol. 2020 Apr 28. pii: S0962-8924(20)30075-1. [Epub ahead of print]

Metabolic Regulation of Tissue Stem Cells.

Suzanne N Shapira, Heather R Christofk.

  Adult tissue stem cells mediate organ homeostasis and regeneration and thus are continually making decisions about whether to remain quiescent, proliferate, or differentiate into mature cell types. These decisions often integrate external cues, such as energy balance and the nutritional status of the organism. Metabolic substrates and byproducts that regulate epigenetic and signaling pathways are now appreciated to have instructive rather than bystander roles in regulating cell fate decisions. In this review, we highlight recent literature focused on how metabolites and dietary manipulations can impact cell fate decisions, with a focus on the regulation of adult tissue stem cells.

Keywords:  adult stem cells; diet; differentiation; metabolism; metabolomics

DOI:  https://doi.org/10.1016/j.tcb.2020.04.004