The hepatic ANGPTL8 (Angiopoietin Like Protein 8) regulatory pathway represents an up-to-date curated interactive pathway for all of the interactions from the known regulators of ANGPTL8 and updated signaling events of insulin signaling in the liver. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3915 CPTAC Assay Portal] Phosphatidylinositol-3,4,5-trisphosphate(PIP3) PTPs catalyze the hydrolysis of the phosphate monoesters specifically on tyrosine residues. Members of the PTP family share a highly conserved catalytic motif, which is essential for the catalytic activity. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP has been shown to act as a negative regulator of insulin signaling by dephosphorylating the phosphotryosine residues of insulin receptor kinase e4b fba ef4 synonyms: RIFL; TD26; PRO1185; PVPA599; C19orf80 bdd d52 ed4 cd6 ed4 cd6 is not affected in human cd6 cd6 Phosphatidylinositol-3,4,5-trisphosphate(PIP3) ad5 dd8 d07 KEGG Pathway hsa04910 c37 b81 PIP3 recruit phosphoinositide-dependent kinase-1 (PDK1) and its substrate kinase Akt to the plasma membrane.PDK1 is believed to be consitutively active There is a broad consensus that PDK1 mediates the T308 phosphorylation of AKT which is independent of the other phosphorylation of Akt. ba9 f32 aed ab8 ac5 bbf ec9 e2e aa3 ad5 ff9 ef4 Experimenst were conducted using Human liver cell lines b8b AMPK phosphorylates TSC2 to activate the complex and in turn inhibit mtorc1. Type your comment here Type your comment here f2b KEGG Pathway hsa04910 c3c ca1 bdc f5e Experimenst were conducted using Human liver cell lines b8b d9b a23 b81 d9b PI3K binds to tyrosine phosphorylated IRS and is activated d7b KEGG Pathway hsa04910 ea1 cc5 e1a d5a Experimenst were conducted using Human liver cell lines b8b d7b KEGG Pathway hsa04919 KEGG Pathway hsa04910" KEGG Pathway hsa04910 aa3 KEGG Pathway hsa04910 f18 f38 bbf SREBP1a and SREBP2 have been show to affect the positive regulation of ANGPTL8 in mice whereas SREBP1c has been reported for same in Humans. Type your comment here d9b cc5 d5a ad5 b81 aed e4b Experimenst were conducted using Human liver cell lines b8b ab8 Foxo1 represses DIO2 during fasting.However the nutritional regulation of insulin signaling pathway leads to its derepression and turning on the conversion of T4 to T3. A combination of animal and cell models were utilized to establish this link.The links has been reported to occur in metabolicacly responsive tisuues including Liver, Brown ADipose tissue and skeletal muscle. Type your comment here Type your comment here Type your comment here c05 c05 b81 e2e KEGG Pathway hsa04910 aa3 KEGG Pathway hsa04910 b81 c37 f2b bbf KEGG Pathway hsa04919 KEGG Pathway hsa04910 b81 In humans 80 percent T3 is contributed via regulation from deiodinases especially DIO2. The local thyroid hormone signaling is coupled with nutritional availaibility via insulin signaling. KEGG Pathway hsa04919 c05 ab8 KEGG Pathway hsa04910 c3c ca1 bdc e2e cee f2b Experimenst were conducted using Human liver cell lines Type your comment here b8b aa3 KEGG Pathway hsa04910 aa3 bbf f2b KEGG Pathway hsa04919 KEGG Pathway hsa04910 KEGG Pathway hsa04910 f18 f18 f38 b81 db9 db9 aed 21440577 PubMed Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta 2011 Hay N 19324998 PubMed Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology 2009 Hashimoto K Ishida E Matsumoto S Okada S Yamada M Satoh T Monden T Mori M 10692429 PubMed Dynamics of protein-tyrosine phosphatases in rat adipocytes. J Biol Chem 2000 Calera MR Vallega G Pilch PF 17234883 PubMed IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback. Genes Dev 2007 Marr MT 2nd D'Alessio JA Puig O Tjian R 26387753 PubMed ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β or Akt-FoxO1 pathway in HepG2 cells. Exp Cell Res 2016 26387753 PubMed ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β or Akt-FoxO1 pathway in HepG2 cells. Exp Cell Res 2016 Rong Guo X Li Wang X Chen Y Hong Yuan Y Mei Chen Y Ding Y Fang J Jiao Bian L Sheng Li D 22927400 PubMed Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci U S A 2012 Owen JL Zhang Y Bae SH Farooqi MS Liang G Hammer RE Goldstein JL Brown MS angiopoietin signaling pathway PW:0000489 Pathway Ontology 16244323 PubMed Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 2005 Kwiatkowski DJ Manning BD 15610735 PubMed A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell 2004 Xu RX Lambert MH Wisely BB Warren EN Weinert EE Waitt GM Williams JD Collins JL Moore LB Willson TM Moore JT 16493415 PubMed Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006 Taniguchi CM Emanuelli B Kahn CR 21908933 PubMed Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review]. Endocr J 2011 Hashimoto K Mori M 23802099 PubMed The Paradox of Akt-mTOR Interactions. Front Oncol 2013 Vadlakonda L Dash A Pasupuleti M Anil Kumar K Reddanna P 22569073 PubMed Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab 2012 Ren G Kim JY Smas CM 23261442 PubMed Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem Biophys Res Commun 2013 Fu Z Yao F Abou-Samra AB Zhang R 8702689 PubMed Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem 1996 Kenner KA Anyanwu E Olefsky JM Kusari J 26569053 PubMed Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down-regulates expression of adipocyte triglyceride lipase. Biochim Biophys Acta 2016 Zhang Y Li S Donelan W Xie C Wang H Wu Q Purich DL Reeves WH Tang D Yang LJ 15581595 PubMed Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys 2005 Handschin C Meyer UA 21453770 PubMed Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors. Biochim Biophys Acta 2011 Poupeau A Postic C 20117946 PubMed The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 2010 Krycer JR Sharpe LJ Luu W Brown AJ 11742412 PubMed Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001 Saltiel AR Kahn CR 25720603 PubMed In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats. Diabetologia 2015 Chen J Chen S Huang P Meng XL Clayton S Shen JS Grayburn PA hepatocyte CL:0000182 Cell Type 24852694 PubMed Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Sci Rep 2014 Fu Z Berhane F Fite A Seyoum B Abou-Samra AB Zhang R 24262987 PubMed Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism. Autophagy 2014 24262987 PubMed Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism. Autophagy 2014 Tseng YH Ke PY Liao CJ Wu SM Chi HC Tsai CY Chen CY Lin YH Lin KH 9228007 PubMed Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997 Stokoe D Stephens LR Copeland T Gaffney PR Reese CB Painter GF Holmes AB McCormick F Hawkins PT 9094314 PubMed Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997 Alessi DR James SR Downes CP Holmes AB Gaffney PR Reese CB Cohen P 8826975 PubMed 24379912 PubMed Betatrophin: A liver-derived hormone for the pancreatic β-cell proliferation. World J Diabetes 2013 Raghow R 26490400 PubMed Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol 2015 Wang Y Viscarra J Kim SJ Sul HS 16916938 PubMed The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Mol Endocrinol 2006 Guo S Dunn SL White MF 27410263 PubMed Resolving Discrepant Findings on ANGPTL8 in β-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy. PLoS One 2016 Cox AR Barrandon O Cai EP Rios JS Chavez J Bonnyman CW Lam CJ Yi P Melton DA Kushner JA 23516131 PubMed A pathway approach to investigate the function and regulation of SREBPs. Genes Nutr 2013 Daemen S Kutmon M Evelo CT 26235620 PubMed A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. Cell Rep 2015 Yang G Murashige DS Humphrey SJ James DE 26499800 PubMed Coupling between Nutrient Availability and Thyroid Hormone Activation 2015 26499800 PubMed Coupling between Nutrient Availability and Thyroid Hormone Activation 2015 Lartey LJ Werneck-de-Castro JP O-Sullivan I Unterman TG Bianco AC insulin signaling pathway PW:0000143 Pathway Ontology regulatory pathway PW:0000004 Pathway Ontology 21908933 PubMed Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review]. Endocr J 2011 Hashimoto K Mori M 26254015 PubMed AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol 2015 Lee J Hong SW Park SE Rhee EJ Park CY Oh KW Park SW Lee WY 11803135 PubMed The role of hepatocyte RXR alpha in xenobiotic-sensing nuclear receptor-mediated pathways. Eur J Pharm Sci 2002 Cai Y Konishi T Han G Campwala KH French SW Wan YJ 11282018 PubMed Insulin signalling. J Cell Sci 2001 Bevan P 19158095 PubMed Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J Biol Chem 2009 Yellaturu CR Deng X Cagen LM Wilcox HG Mansbach CM 2nd Siddiqi SA Park EA Raghow R Elam MB 20412774 PubMed FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010 Chen CC Jeon SM Bhaskar PT Nogueira V Sundararajan D Tonic I Park Y Hay N 11875109 PubMed Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol Endocrinol 2002 Li Y Bolten C Bhat BG Woodring-Dietz J Li S Prayaga SK Xia C Lala DS 19683471 PubMed Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 2009 Tanti JF Jager J 20698033 PubMed AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability. World J Gastroenterol 2010 Yang YM Han CY Kim YJ Kim SG 23150577 PubMed Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci U S A 2012 Quagliarini F Wang Y Kozlitina J Grishin NV Hyde R Boerwinkle E Valenzuela DM Murphy AJ Cohen JC Hobbs HH 21310851 PubMed MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feedback loop of LXRα autoregulation. Mol Endocrinol 2011 Ou Z Wada T Gramignoli R Li S Strom SC Huang M Xie W