KEGG   PATHWAY: ko04922
Entry
ko04922                     Pathway                                
Name
Glucagon signaling pathway
Description
Glucagon is conventionally regarded as a counterregulatory hormone for insulin and plays a critical anti-hypoglycemic role by maintaining glucose homeostasis in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Glucagon also stimulates hepatic mitochondrial beta-oxidation to supply energy for glucose production. Glucagon performs its main effect via activation of adenylate cyclase. The adenylate-cyclase-derived cAMP activates protein kinase A (PKA), which then phosphorylates downstream targets, such as cAMP response element binding protein (CREB) and the bifunctional enzyme 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (one of the isoforms being PFK/FBPase 1, encoded by PFKFB1).
Class
Organismal Systems; Endocrine system
Pathway map
ko04922  Glucagon signaling pathway
ko04922

Orthology
K00016  LDH; L-lactate dehydrogenase [EC:1.1.1.27]
K00161  PDHA; pyruvate dehydrogenase E1 component subunit alpha [EC:1.2.4.1]
K00162  PDHB; pyruvate dehydrogenase E1 component subunit beta [EC:1.2.4.1]
K00688  PYG, glgP; glycogen phosphorylase [EC:2.4.1.1]
K00693  GYS; glycogen synthase [EC:2.4.1.11]
K00850  pfkA, PFK; 6-phosphofructokinase 1 [EC:2.7.1.11]
K00871  PHKG; phosphorylase kinase gamma subunit [EC:2.7.11.19]
K00873  PK, pyk; pyruvate kinase [EC:2.7.1.40]
K01084  G6PC; glucose-6-phosphatase [EC:3.1.3.9]
K01596  E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32]
K01834  PGAM, gpmA; 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase [EC:5.4.2.11]
K01946  ACACB; acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15]
K02183  CALM; calmodulin
K03841  FBP; fructose-1,6-bisphosphatase I [EC:3.1.3.11]
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04348  PPP3C, CNA; serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K04374  ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04450  ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04456  AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04498  EP300, CREBBP, KAT3; E1A/CREB-binding protein [EC:2.3.1.48]
K04515  CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04583  GCGR; glucagon receptor
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04958  ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959  ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K05259  GCG; glucagon
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K05870  CREB1; cyclic AMP-responsive element-binding protein 1
K06268  PPP3R, CNB; serine/threonine-protein phosphatase 2B regulatory subunit
K07190  PHKA_B; phosphorylase kinase alpha/beta subunit
K07198  PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31]
K07199  PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit
K07200  PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit
K07201  FOXO1; forkhead box protein O1
K07202  PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K07294  NR1C1, PPARA; peroxisome proliferator-activated receptor alpha
K07299  SLC2A1, GLUT1; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1
K07593  SLC2A2, GLUT2; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08765  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [EC:2.3.1.21]
K09047  CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048  CREB3; cyclic AMP-responsive element-binding protein 3
K11262  ACACA; acetyl-CoA carboxylase / biotin carboxylase 1 [EC:6.4.1.2 6.3.4.14 2.1.3.15]
K11411  SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286]
K11434  PRMT1; type I protein arginine methyltransferase [EC:2.1.1.319]
K12407  GCK; glucokinase [EC:2.7.1.2]
K13296  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17]
K15423  PPP4C; serine/threonine-protein phosphatase 4 catalytic subunit [EC:3.1.3.16]
K16311  SIK2; serine/threonine-protein kinase SIK2 [EC:2.7.11.1]
K16333  CRTC2, TORC2; CREB-regulated transcription coactivator 2
K17491  SMEK, PPP4R3; protein phosphatase 4 regulatory subunit 3
K19008  SIK1; serine/threonine-protein kinase SIK1 [EC:2.7.11.1]
K19028  PFKFB1; 6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 1 [EC:2.7.1.105 3.1.3.46]
K19523  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21]
K19524  CPT1C; carnitine O-palmitoyltransferase 1, brain isoform [EC:2.3.1.21]
Compound
C00022  Pyruvate
C00024  Acetyl-CoA
C00026  2-Oxoglutarate
C00031  D-Glucose
C00036  Oxaloacetate
C00040  Acyl-CoA
C00042  Succinate
C00074  Phosphoenolpyruvate
C00076  Calcium cation
C00083  Malonyl-CoA
C00085  D-Fructose 6-phosphate
C00103  D-Glucose 1-phosphate
C00122  Fumarate
C00149  (S)-Malate
C00158  Citrate
C00182  Glycogen
C00186  (S)-Lactate
C00197  3-Phospho-D-glycerate
C00311  Isocitrate
C00354  D-Fructose 1,6-bisphosphate
C00575  3',5'-Cyclic AMP
C00631  2-Phospho-D-glycerate
C00665  beta-D-Fructose 2,6-bisphosphate
C00668  alpha-D-Glucose 6-phosphate
C01172  beta-D-Glucose 6-phosphate
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:12626323
  Authors
Jiang G, Zhang BB
  Title
Glucagon and regulation of glucose metabolism.
  Journal
Am J Physiol Endocrinol Metab 284:E671-8 (2003)
DOI:10.1152/ajpendo.00492.2002
Reference
PMID:24692138
  Authors
Rui L
  Title
Energy metabolism in the liver.
  Journal
Compr Physiol 4:177-97 (2014)
DOI:10.1002/cphy.c130024
Reference
PMID:22004992
  Authors
Jitrapakdee S
  Title
Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis.
  Journal
Int J Biochem Cell Biol 44:33-45 (2012)
DOI:10.1016/j.biocel.2011.10.001
Reference
PMID:16601267
  Authors
Desvergne B, Michalik L, Wahli W.
  Title
Transcriptional regulation of metabolism.
  Journal
Physiol Rev 86:465-514 (2006)
DOI:10.1152/physrev.00025.2005
Reference
PMID:22550228
  Authors
Hardie DG
  Title
Organismal carbohydrate and lipid homeostasis.
  Journal
Cold Spring Harb Perspect Biol 4:a006031 (2012)
DOI:10.1101/cshperspect.a006031
Reference
PMID:22796337
  Authors
Hasenour CM, Berglund ED, Wasserman DH
  Title
Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver.
  Journal
Mol Cell Endocrinol 366:152-62 (2013)
DOI:10.1016/j.mce.2012.06.018
Reference
PMID:18669612
  Authors
Quesada I, Tuduri E, Ripoll C, Nadal A
  Title
Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes.
  Journal
J Endocrinol 199:5-19 (2008)
DOI:10.1677/JOE-08-0290
Reference
PMID:24238363
  Authors
Oh KJ, Han HS, Kim MJ, Koo SH
  Title
CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis.
  Journal
BMB Rep 46:567-74 (2013)
DOI:10.5483/BMBRep.2013.46.12.248
Reference
PMID:16479585
  Authors
Cheng A, Saltiel AR
  Title
More TORC for the gluconeogenic engine.
  Journal
Bioessays 28:231-4 (2006)
DOI:10.1002/bies.20375
Reference
PMID:21346730
  Authors
Altarejos JY, Montminy M
  Title
CREB and the CRTC co-activators: sensors for hormonal and metabolic signals.
  Journal
Nat Rev Mol Cell Biol 12:141-51 (2011)
DOI:10.1038/nrm3072
Reference
PMID:24393785
  Authors
Pernicova I, Korbonits M
  Title
Metformin--mode of action and clinical implications for diabetes and cancer.
  Journal
Nat Rev Endocrinol 10:143-56 (2014)
DOI:10.1038/nrendo.2013.256
Reference
PMID:20735177
  Authors
Hirota K, Fukamizu A
  Title
Transcriptional regulation of energy metabolism in the liver.
  Journal
J Recept Signal Transduct Res 30:403-9 (2010)
DOI:10.3109/10799893.2010.509730
Reference
PMID:21941300
  Authors
Chalkiadaki A, Guarente L
  Title
Metabolic signals regulate SIRT1 expression.
  Journal
EMBO Rep 12:985-6 (2011)
DOI:10.1038/embor.2011.179
Reference
PMID:22249520
  Authors
Chalkiadaki A, Guarente L
  Title
Sirtuins mediate mammalian metabolic responses to nutrient availability.
  Journal
Nat Rev Endocrinol 8:287-96 (2012)
DOI:10.1038/nrendo.2011.225
Reference
PMID:19912989
  Authors
Tang BL, Chua CE
  Title
Is systemic activation of Sirt1 beneficial for ageing-associated metabolic disorders?
  Journal
Biochem Biophys Res Commun 391:6-10 (2010)
DOI:10.1016/j.bbrc.2009.11.016
Reference
PMID:22503562
  Authors
Ozcan L, Wong CC, Li G, Xu T, Pajvani U, Park SK, Wronska A, Chen BX, Marks AR, Fukamizu A, Backs J, Singer HA, Yates JR 3rd, Accili D, Tabas I
  Title
Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.
  Journal
Cell Metab 15:739-51 (2012)
DOI:10.1016/j.cmet.2012.03.002
Reference
PMID:22495310
  Authors
Wang Y, Li G, Goode J, Paz JC, Ouyang K, Screaton R, Fischer WH, Chen J, Tabas I, Montminy M
  Title
Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.
  Journal
Nature 485:128-32 (2012)
DOI:10.1038/nature10988
Related
pathway
ko00010  Glycolysis / Gluconeogenesis
ko00020  Citrate cycle (TCA cycle)
ko00061  Fatty acid biosynthesis
ko00190  Oxidative phosphorylation
ko04020  Calcium signaling pathway
ko04024  cAMP signaling pathway
ko04068  FoxO signaling pathway
ko04910  Insulin signaling pathway

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