Angiopoietin-like protein 8 regulatory pathway (WP3915)

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]
last edited

Authors

Siddiqa, Susan, Elisa, Khanspers, Egonw, AlexanderPico, MaintBot, Marvin M2, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: insulin signaling pathway regulatory pathway

Participants

Label Type Compact Identifier
PI(3,4,5)P3 Metabolite kegg.compound:C05981
PIK3CD GeneProduct ncbigene:5293
PIK3C3 GeneProduct ncbigene:5289
PTP GeneProduct ncbigene:5770
IRS1 GeneProduct ncbigene:3667
GLUT1 GeneProduct ncbigene:6513
PPARalpha GeneProduct None
AMPKPathway Pathway wikipathways:WP1403
FBP GeneProduct ncbigene:2203
GS GeneProduct ncbigene:2997
X-5-P Metabolite kegg.compound:C00231
RHEB GeneProduct ncbigene:6009
PI(4,5)P2 Metabolite kegg.compound:C04637
G6PC GeneProduct ncbigene:2538
PIK3R3 GeneProduct ncbigene:8503
CD45+ hematopoietic- derived cell proliferation Pathway wikipathways:WP2849
PIK3R1 GeneProduct ncbigene:5295
PEPCK GeneProduct ncbigene:5105
IRS2 GeneProduct ncbigene:8660
PIK3C2G GeneProduct ncbigene:5288
PIK3R2 GeneProduct ncbigene:5296
Glycolysis-Gluconeogenesis Pathway wikipathways:WP534
Insulin Signaling Pathway Pathway None
Glucose Metabolite kegg.compound:C00031
Autophagy Signaling Pathway None
INSR GeneProduct ncbigene:3643
RPS6KB2 GeneProduct ncbigene:6199
SOS1 GeneProduct ncbigene:6654
PIK3CG GeneProduct ncbigene:5294
IRS4 GeneProduct ncbigene:8471
TSC2 GeneProduct ncbigene:7249
PIK3CB GeneProduct ncbigene:5291
SIN1 GeneProduct ncbigene:79109
Chrebp GeneProduct ncbigene:51085
GLUT4 GeneProduct ncbigene:6517
CIP42 GeneProduct ncbigene:9322
TSC1 GeneProduct ncbigene:7248
Raptor GeneProduct ncbigene:57521
glycogen Metabolite kegg.compound:C00369
Glycogenesis Pathway None
RPS6KB1 GeneProduct ncbigene:6198
SREBP1a-c GeneProduct ensembl:ENSG00000072310
LPL GeneProduct ncbigene:4023
mlst8 GeneProduct ncbigene:64223
G-6-P Metabolite kegg.compound:C00092
GCK GeneProduct kegg.genes:2645
Rictor GeneProduct ncbigene:253260
Insulin Protein uniprot:A6XGL2
Triacylglyceride Synthesis Pathway kegg.pathway:WP325
PIK3R4 GeneProduct ncbigene:30849
RAS GeneProduct ncbigene:3265
LXR GeneProduct ncbigene:10062
SOS2 GeneProduct ncbigene:6655
Exo70 GeneProduct ncbigene:23265
RAF1 GeneProduct ncbigene:5894
Protein synthesis and Translation Regulation Pathway None
SREBP2 GeneProduct ensembl:ENSG00000198911
mTOR GeneProduct ncbigene:2475
SEST3 GeneProduct ncbigene:143686
mTOR GeneProduct ncbigene:2475
SREBP Pathway Pathway wikipathways:WP1982
PP2A GeneProduct None
GRB2 GeneProduct None
PIK3C2A GeneProduct ncbigene:5286
Cell GrowthDifferentiation Pathway wikipathways:WP2029
PIK3CA GeneProduct ncbigene:5290
amino acids Metabolite chebi:33709
F-2,6-P2 Metabolite kegg.compound:C00665
DIO2 GeneProduct ncbigene:1734
RXRA GeneProduct ncbigene:6256
THRA GeneProduct ncbigene:7067
THRB GeneProduct ncbigene:7068
SLC16A2 GeneProduct ncbigene:6567
SLCO1C1 GeneProduct ncbigene:53919
T3 Metabolite chemspider:5707
T4 Metabolite hmdb:HMDB0000248
RXRA GeneProduct ncbigene:6256
ANGPTL8 GeneProduct ncbigene:55908
SHC2 GeneProduct ncbigene:25759
SHC3 GeneProduct ncbigene:53358
SHC1 GeneProduct ncbigene:6464
GSK3A GeneProduct ncbigene:2931
GSK3B GeneProduct ncbigene:2932
PDK GeneProduct ncbigene:5170
AKT1 GeneProduct ncbigene:207
AKT2 GeneProduct ncbigene:208
EIF4E GeneProduct ncbigene:1977
EIF4EBP1 GeneProduct ncbigene:1978
mlst8 GeneProduct ncbigene:64223
mTOR GeneProduct ncbigene:2475
SIN1 GeneProduct ncbigene:79109
Rictor GeneProduct ncbigene:253260
mlst8 GeneProduct ncbigene:64223
FOXO1A GeneProduct ncbigene:2308
FOXO3A GeneProduct ncbigene:2309
INSR GeneProduct ncbigene:3643
CAP1 GeneProduct ncbigene:10487
CBL GeneProduct ncbigene:867
FLOT1 GeneProduct ncbigene:10211
FLOT2 GeneProduct ncbigene:2319
CRK GeneProduct ncbigene:1398
RAPGEF1 GeneProduct ncbigene:2889
RHOQ GeneProduct ncbigene:23433
Rictor GeneProduct ncbigene:253260
RXRA GeneProduct ensembl:ENSG00000186350
ABCG8 GeneProduct ensembl:ENSG00000143921
FASN GeneProduct ensembl:ENSG00000169710
ABCG5 GeneProduct ensembl:ENSG00000138075
CYP3A4 GeneProduct ensembl:ENSG00000160868
CYP7A1 GeneProduct ensembl:ENSG00000167910
CYP2B6 GeneProduct ensembl:ENSG00000197408
Drug and steroidmetabolism Pathway None
Multi-drugresistance Pathway None
lipogenesis Pathway None
SCD GeneProduct ensembl:ENSG00000099194
Transcriptionfactors Pathway None
MAP2K1 GeneProduct ncbigene:5604
MAP3K7 GeneProduct ncbigene:6885
MAPK14 GeneProduct ncbigene:1432
MAPK1 GeneProduct ncbigene:5594
MAP2K2 GeneProduct ncbigene:5605
RPS6KA5 GeneProduct ncbigene:9252
MAP3K2 GeneProduct ncbigene:10746
MAP3K6 GeneProduct ncbigene:9064
MAPK8 GeneProduct ncbigene:5599
MAP4K1 GeneProduct ncbigene:11184
MAP3K11 GeneProduct ncbigene:4296
MAP4K3 GeneProduct ncbigene:8491
MAPK10 GeneProduct ncbigene:5602
RPS6KA6 GeneProduct ncbigene:27330
MAP2K7 GeneProduct ncbigene:5609
MAP3K4 GeneProduct ncbigene:4216
MAP3K1 GeneProduct ncbigene:4214
MAP3K12 GeneProduct ncbigene:7786
MAPK4 GeneProduct ncbigene:5596
RPS6KA4 GeneProduct ncbigene:8986
MAPK11 GeneProduct ncbigene:5600
MAP4K5 GeneProduct ncbigene:11183
MAPK6 GeneProduct ncbigene:5597
MAP4K4 GeneProduct ncbigene:9448
MAPK3 GeneProduct ncbigene:5595
MAP3K14 GeneProduct ncbigene:9020
MAPK12 GeneProduct ncbigene:6300
MAP2K5 GeneProduct ncbigene:5607
MAP2K4 GeneProduct ncbigene:6416
MAPK13 GeneProduct ncbigene:5603
RPS6KA1 GeneProduct ncbigene:6195
RPS6KA2 GeneProduct ncbigene:6196
MAP3K5 GeneProduct ncbigene:4217
RPS6KA3 GeneProduct ncbigene:6197
MAPK9 GeneProduct ncbigene:5601
MAPK7 GeneProduct ncbigene:5598
MAP3K3 GeneProduct ncbigene:4215
MAP3K9 GeneProduct ncbigene:4293
MAP3K8 GeneProduct ncbigene:1326
MAP2K6 GeneProduct ncbigene:5608
MAP3K13 GeneProduct ncbigene:9175
MAP4K2 GeneProduct ncbigene:5871
MAP2K3 GeneProduct ncbigene:5606
MAP3K10 GeneProduct ncbigene:4294
MINK1 GeneProduct ncbigene:50488
PI(3,4,5)P3 Metabolite kegg.compound:C05981
AKT1 GeneProduct ncbigene:207
AKT2 GeneProduct ncbigene:208
CBLC GeneProduct ncbigene:23624
CBLB GeneProduct ncbigene:868
FOXO1A GeneProduct ncbigene:2308
FOXO3A GeneProduct ncbigene:2309
Insulin Protein uniprot:A6XGL2
INSR GeneProduct ncbigene:3643
Insulin Signaling Pathway Pathway wikipathways:WP1982
AMPKy3 GeneProduct ncbigene:53632
AMPKa1 GeneProduct ncbigene:5562
AMPKy2 GeneProduct ncbigene:51422
AMPKy1 GeneProduct ncbigene:5571
AMPKb2 GeneProduct ncbigene:5565
AMPKb1 GeneProduct ncbigene:5564
AMPKa2 GeneProduct ncbigene:5563

References

  1. Kenner KA, Anyanwu E, Olefsky JM, Kusari J. Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem. 1996 Aug 16;271(33):19810–6. PubMed Europe PMC Scholia
  2. Seely BL, Staubs PA, Reichart DR, Berhanu P, Milarski KL, Saltiel AR, et al. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes. 1996 Oct;45(10):1379–85. PubMed Europe PMC Scholia
  3. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997 Apr 1;7(4):261–9. PubMed Europe PMC Scholia
  4. Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997 Jul 25;277(5325):567–70. PubMed Europe PMC Scholia
  5. Calera MR, Vallega G, Pilch PF. Dynamics of protein-tyrosine phosphatases in rat adipocytes. J Biol Chem. 2000 Mar 3;275(9):6308–12. PubMed Europe PMC Scholia
  6. Bevan P. Insulin signalling. J Cell Sci. 2001 Apr;114(Pt 8):1429–30. PubMed Europe PMC Scholia
  7. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001 Dec 13;414(6865):799–806. PubMed Europe PMC Scholia
  8. Cai Y, Konishi T, Han G, Campwala KH, French SW, Wan Y-JY. The role of hepatocyte RXR alpha in xenobiotic-sensing nuclear receptor-mediated pathways. Eur J Pharm Sci. 2002 Feb;15(1):89–96. PubMed Europe PMC Scholia
  9. Li Y, Bolten C, Bhat BG, Woodring-Dietz J, Li S, Prayaga SK, et al. Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol Endocrinol. 2002 Mar;16(3):506–14. PubMed Europe PMC Scholia
  10. Handschin C, Meyer UA. Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys. 2005 Jan 15;433(2):387–96. PubMed Europe PMC Scholia
  11. Xu RX, Lambert MH, Wisely BB, Warren EN, Weinert EE, Waitt GM, et al. A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell. 2004 Dec 22;16(6):919–28. PubMed Europe PMC Scholia
  12. Kwiatkowski DJ, Manning BD. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R251-8. PubMed Europe PMC Scholia
  13. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006 Feb;7(2):85–96. PubMed Europe PMC Scholia
  14. Guo S, Dunn SL, White MF. The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Mol Endocrinol. 2006 Dec;20(12):3389–99. PubMed Europe PMC Scholia
  15. Marr MT 2nd, D’Alessio JA, Puig O, Tjian R. IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback. Genes Dev. 2007 Jan 15;21(2):175–83. PubMed Europe PMC Scholia
  16. Hashimoto K, Ishida E, Matsumoto S, Okada S, Yamada M, Satoh T, et al. Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology. 2009 Jul;150(7):3417–24. PubMed Europe PMC Scholia
  17. Tanti J-F, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009 Dec;9(6):753–62. PubMed Europe PMC Scholia
  18. Chen C-C, Jeon S-M, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell. 2010 Apr 20;18(4):592–604. PubMed Europe PMC Scholia
  19. Yang YM, Han CY, Kim YJ, Kim SG. AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability. World J Gastroenterol. 2010 Aug 14;16(30):3731–42. PubMed Europe PMC Scholia
  20. Ou Z, Wada T, Gramignoli R, Li S, Strom SC, Huang M, et al. MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feedback loop of LXRα autoregulation. Mol Endocrinol. 2011 Apr;25(4):584–96. PubMed Europe PMC Scholia
  21. Hay N. Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta. 2011 Nov;1813(11):1965–70. PubMed Europe PMC Scholia
  22. Poupeau A, Postic C. Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors. Biochim Biophys Acta. 2011 Aug;1812(8):995–1006. PubMed Europe PMC Scholia
  23. Hashimoto K, Mori M. Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review]. Endocr J. 2011;58(11):921–30. PubMed Europe PMC Scholia
  24. Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012 Aug 1;303(3):E334-51. PubMed Europe PMC Scholia
  25. Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci U S A. 2012 Nov 27;109(48):19751–6. PubMed Europe PMC Scholia
  26. Fu Z, Yao F, Abou-Samra AB, Zhang R. Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem Biophys Res Commun. 2013 Jan 18;430(3):1126–31. PubMed Europe PMC Scholia
  27. Daemen S, Kutmon M, Evelo CT. A pathway approach to investigate the function and regulation of SREBPs. Genes Nutr. 2013 May;8(3):289–300. PubMed Europe PMC Scholia
  28. Yi P, Park J-S, Melton DA. Betatrophin: a hormone that controls pancreatic β cell proliferation. Cell. 2013 May 9;153(4):747–58. PubMed Europe PMC Scholia
  29. Vadlakonda L, Dash A, Pasupuleti M, Anil Kumar K, Reddanna P. The Paradox of Akt-mTOR Interactions. Front Oncol. 2013 Jun 20;3:165. PubMed Europe PMC Scholia
  30. Tseng Y-H, Ke P-Y, Liao C-J, Wu S-M, Chi H-C, Tsai C-Y, et al. Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism. Autophagy. 2014 Jan;10(1):20–31. PubMed Europe PMC Scholia
  31. Raghow R. Betatrophin: A liver-derived hormone for the pancreatic β-cell proliferation. World J Diabetes. 2013 Dec 15;4(6):234–7. PubMed Europe PMC Scholia
  32. Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB, Zhang R. Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Sci Rep. 2014 May 23;4:5013. PubMed Europe PMC Scholia
  33. Chen J, Chen S, Huang P, Meng X-L, Clayton S, Shen J-S, et al. In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats. Diabetologia. 2015 May;58(5):1036–44. PubMed Europe PMC Scholia
  34. Yang G, Murashige DS, Humphrey SJ, James DE. A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. Cell Rep. 2015 Aug 11;12(6):937–43. PubMed Europe PMC Scholia
  35. Lee J, Hong S-W, Park SE, Rhee E-J, Park C-Y, Oh K-W, et al. AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol. 2015 Oct 15;414:148–55. PubMed Europe PMC Scholia
  36. Rong Guo X, Li Wang X, Chen Y, Hong Yuan Y, Mei Chen Y, Ding Y, et al. ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β or Akt-FoxO1 pathway in HepG2 cells. Exp Cell Res. 2016 Jul 15;345(2):158–67. PubMed Europe PMC Scholia
  37. Wang Y, Viscarra J, Kim S-J, Sul HS. Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol. 2015 Nov;16(11):678–89. PubMed Europe PMC Scholia
  38. Lartey LJ, Werneck-de-Castro JP, O-Sullivan I, Unterman TG, Bianco AC. Coupling between Nutrient Availability and Thyroid Hormone Activation. J Biol Chem. 2015 Dec 18;290(51):30551–61. PubMed Europe PMC Scholia
  39. Zhang Y, Li S, Donelan W, Xie C, Wang H, Wu Q, et al. Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down-regulates expression of adipocyte triglyceride lipase. Biochim Biophys Acta. 2016 Feb;1861(2):130–7. PubMed Europe PMC Scholia
  40. Cox AR, Barrandon O, Cai EP, Rios JS, Chavez J, Bonnyman CW, et al. Resolving Discrepant Findings on ANGPTL8 in β-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy. PLoS One. 2016 Jul 13;11(7):e0159276. PubMed Europe PMC Scholia