CST Guide:

Section I: Research Areas
Insulin Receptor Signaling
Glucose
GLUT4
PDK1
Bad
SGK
Apoptosis
ENaC
Sodium
Transport
Cytoplasm
Nucleus
GLUT4
Translocation
GLUT4
vesicle
GLUT4
Exocytosis
PP1
mTORC1
GβL Raptor
mTOR
DEPTOR
FoxO3
SNARE
Complex
Synip
TC10
CIP4/2
GSK-3
SGK
Crkll
PP2A
14-3-3
AS160
TBC1D1
14-3-3
GS
Glycogen
Synthesis
Transcription
CAP
C3G
Rac1
ATP-citrate
lyase
FoxO4
Flotillin
Cav
SREBP
Fatty Acid
Synthesis
mTORC2
Sin1 PRR5
Rictor GβL
mTOR
DEPTOR
Cbl
APS
EHD1
EHBP1
PKCλ/ζ
Lipin1
Akt2
FoxO1
PDK1
PTEN
SHIP
PRAS40
Apoptosis,
Autophagy,
Glucose and
Lipid Metabolism
4E-BP1
PIP 3
Akt
TSC2
TSC1
Rheb
p85
PI3K
p110
144 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
Gab1
SHP-2
IRS
Shc
GRB2
IRS-1
eIF4E
HSL
Protein Synthesis,
Growth, and SREBP-1
Proliferation
Lipolysis
Lipin1
Akt2
mTORC2
mTORC1
Fatty Acid
and Cholesterol
Synthesis
PKCλ/ζ
LKB1
AMPK
SREBP
p70
S6K
Erk1/2
LXRα
PDE3B
[cAMP]
PKA
USF
Insulin Receptor
PKCθ
FFA
NO
SIK2
SOCS3
Nck
Crkll
Fyn
IKK
ROS
CBP/p300
PTP1B
iNOS
Jnk
Torc2
Disruption of
CBP/Torc2/CREB
Complex
Gluconeogenesis
TNFR1
TNF
GRB10
Degradation
SOS
Ras
c-Raf
MEK1/2
Erk1/2
Erk1/2
Growth
Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin activates the insulin receptor tyrosine kinase (IR), which
phosphorylates and recruits different substrate adaptors such as the IRS family of proteins. Tyrosine phosphorylated IRS then displays binding sites for numerous signaling
partners. Among them, PI3K has a major role in insulin function, mainly via the activation of the Akt/PKB and the PKCζ cascades. Activated Akt induces glycogen synthesis
through inhibition of GSK-3; protein synthesis via mTOR and downstream elements; and cell survival through inhibition of several pro-apoptotic agents (Bad, FoxO transcription
factors, GSK-3, and MST1). Akt phosphorylates and directly inhibits FoxO transcription factors, which also regulate metabolism and autophagy. Inversely, AMPK is known to
directly regulate FoxO3 and activate transcriptional activity. Insulin signaling also has growth and mitogenic effects, which are mostly mediated by the Akt cascade as well as
by activation of the Ras/MAPK pathway. The insulin signaling pathway inhibits autophagy via the ULK1 kinase, which is inhibited by Akt and mTORC1, and activated by AMPK.
Insulin stimulates glucose uptake in muscle and adipocytes via translocation of GLUT4 vesicles to the plasma membrane. GLUT4 translocation involves the PI3K/Akt pathway
and IR-mediated phosphorylation of CAP, and formation of the CAP:CBL:CRKII complex. In addition, insulin signaling inhibits gluconeogenesis in the liver, through disruption
of CREB/CBP/mTORC2 binding. Insulin signaling induces fatty acid and cholesterol synthesis via the regulation of SREBP transcription factors. Insulin signaling also promotes
fatty acid synthesis through activation of USF1 and LXR. A negative feedback signal emanating from Akt/PKB, PKCζ, p70 S6K, and the MAPK cascades results in serine
phosphorylation and inactivation of IRS signaling.
Select Reviews:
Altarejos, J.Y. and Montminy, M. (2011) Nat. Rev. Mol. Cell Biol. 12, 141–151. • Cheng, Z., Tseng, Y., and White, M.F. (2010) Trends Endocrinol. Metab. 21, 589–958.
• Fritsche, L., Weigert, C., Häring, H.U., and Lehmann, R. (2008) Curr. Med. Chem. 15, 1316–1329. • Guo, S. (2014) J. Endocrinol. 220,T1–T23. • Rowland, A.F.,
Fazakerley, D.J., and James, D.E. (2011) Traffic 12, 672–681. • Siddle, K. (2011) J. Mol. Endocrinol. 47, R1–R10. • Shao, W. and Espenshade, P.J. (2012) Cell Metab.
16, 414–419. • Wong, R.H. and Sul, H.S. (2010) Curr. Opin. Pharmacol. 10, 684–691.
© 2003–2015 Cell Signaling Technology, Inc. • We would like to thank Ashley Webb and Prof. Anne Brunet Stanford University, Palo Alto, CA for reviewing this diagram.
Warburg Effect
Pentose
Phosphate
Shunt
NADPH
Ribulose-5P
Nucleotide
Synthesis
NADPH
Folate
Metabolism
6-P-
NADP
Gluconate
Glycine
NADP
Macropinocytosis and
other scavenging pathways
Malic Enzyme
Akt
Amino Acids
and Lipids
Serine
Malate
Hexokinase
NADP
PHGDH
OMM Stability
Inhibition Cytochrome C Release
Inhibition of Apoptosis
Bax
NADPH
NADPH
6-P-
Gluconolactone
p53
ANT
VDAC
VDAC
Lactate
ANT
TIGAR
HIF-1α
c-Myc
NADP
Malate
Glucose
Transporters
Hexokinase
Glucose-6-P
Fructose-6-P
PFK
Fructose
Bisphosphate
3-Phosphoglycerate
p53
Glycolysis
Glucose
PEP
PKM2
Pyruvate
IDH2
Ras
Citrate
UCP2
Ras
LDHA
Pyruvate PDHK
Dehydrogenase
Pyruvate
Acetyl-CoA
Oxaloacetate
Krebs
Cycle
α-Ketoglutarate
AMPK
c-Myc
c-Myc
ULK1
NADP
Glutaminase
NADPH
Glutamine Transporters
Glutamine
Glutaminolysis
LKB1
Protein Synthesis
chapter 05: cellular metabolism
Growth Factors
PI3K
Akt
mTOR
Autophagy
β-Oxidation
Citrate
ACL
Acetyl-CoA
IDH1 ACC
Epigenetic
Regulation
Ras
Amino Acids
SREBP
HIF-1α
Cell Proliferation
MEK1/2
Erk1/2
c-Myc
Fatty Acid Oxidation
Fatty Acids
Acetate
ACSS2
AMPK
Fatty Acid/
Lipid Synthesis
Cancer cells rely on a variety of metabolic fuels, and the specific nutrients used are impacted by both the genetic and environmental context of the cancer cell.
Most mammalian cells use glucose as a fuel source. Glucose is metabolized by glycolysis in a multistep set of reactions resulting in the creation of pyruvate. In typical cells
under normal oxygen levels, much of this pyruvate enters the mitochondria where it is oxidized by the Krebs Cycle to generate ATP to meet the cell’s energy demands. However,
in cancer cells or other highly proliferative cell types, much of the pyruvate from glycolysis is directed away from the mitochondria to create lactate through the action of
lactate dehydrogenase (LDH/LDHA)—a process typically reserved for the low oxygen state. Lactate production in the presence of oxygen is termed “aerobic glycolysis” or the
Warburg Effect.
Cancer cells frequently use glutamine as another fuel source, which enters the mitochondria and can be used to replenish Krebs Cycle intermediates or to produce more pyruvate
through the action of malic enzyme. Highly proliferative cells need to produce excess lipid, nucleotide, and amino acids for the creation of new biomass. Excess glucose is
diverted through the pentose phosphate shunt (PPS) and serine/glycine biosynthesis pathway to create nucleotides. Fatty acids are critical for new membrane production and
are synthesized from citrate in the cytosol by ATP-citrate lyase (ACL) to generate acetyl-CoA. Acetate can also be a source of carbon for acetyl-CoA production when available.
De novo lipid synthesis requires NADPH reducing equivalents, which can be generated through the actions of malic enzyme, IDH1, and also from multiple steps within the PPS
pathway and serine/glycine metabolism. These reducing equivalents are also part of the defense against the increased levels of reactive oxygen species that are characteristic
of cancer cells. There is also evidence that some cancer cells can scavenge extracellular protein, amino acids, and lipids. Macropinocytosis, a process that allows bulk uptake
of extracellular material that can be delivered to the lysosome, is one way the cells can catabolize extracellular material and provide nutrients for cell metabolism. These
nutrients can generate ATP or NADPH, or contribute directly to biomass.
Several signaling pathways contribute to the Warburg Effect and other metabolic phenotypes of cancer cells. Growth factor stimulation results in signaling through RTKs to
activate PI3K/Akt and Ras. Akt promotes glucose transporter activity and stimulates glycolysis through activation of several glycolytic enzymes including hexokinase and phosphofructokinase
(PFK). Akt phosphorylation of apoptotic proteins such as Bax makes cancer cells resistant to apoptosis and helps stabilize the outer mitochondrial membrane
(OMM) by promoting attachment of mitochondrial hexokinase (mtHK) to the VDAC channel complex. RTK signaling to c-Myc results in transcriptional activation of numerous
genes involved in glycolysis and lactate production. The p53 oncogene transactivates TP-53-induced Glycolysis and Apoptosis Regulator (TIGAR) and results in increased
NADPH production by PPS. Signals impacting levels of hypoxia inducible factor (HIF) can increase expression of enzymes such as LDHA to promote lactate production, as
well as pyruvate dehydrogenase kinase to inhibit the action of pyruvate dehydrogenase and limit entry of pyruvate into the Krebs Cycle. There is also increasing evidence that
availability of metabolic substrates can influence gene expression by affecting epigenetic marks on histones and DNA.
Select Reviews:
Dang, C.V., Le, A., and Gao, P. (2009) Clin. Cancer Res. 15, 6479–6483. • Gogvadze, V., Zhivotovsky, B., and Orrenius, S. (2010) Mol. Aspects Med. 31, 60–74. •
Hensley, C.T., Wasti, A.T., and DeBerardinis, R.J. (2013) J. Clin. Invest. 123, 3678–3684. • Kaelin, W.G. Jr. and McKnight, S.L. (2013) Cell 153, 56–69. • Lunt, S.Y. and
Vander Heiden, M.G. (2011) Annu. Rev. Cell Dev. Biol. 27, 441–464. • Samudio, I., Fiegl, M., and Andreeff, M. (2009) Cancer Res. 69, 2163–2166. • Tennant, D.A.,
Durán, R.V., and Gottlieb, E. (2010) Nat. Rev. Cancer 10, 267–277. • White, E. (2013) Genes Dev. 27, 2065–2071. • Vander Heiden, M.G., Cantley, L.C., and Thompson,
C.B. (2009) Science 324, 1029–1033.
© 2010–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Matthew G. Vander Heiden, Massachusetts Institute of Technology, Cambridge, MA for reviewing this diagram.
www.cellsignal.com/cstpathways 145