EGF Signaling: Tracing Cancer's Path | Biowire Fall 2011


 

Biowire Fall 2011 — Screening — microRNA Target Identification

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The epidermal growth factor (EGF) family is a group of structurally related proteins that regulate cell proliferation, migration and differentiation via tyrosine kinase receptors on target cells. The EGF receptor has a cytoplasmic tyrosine kinase domain, a transmembrane domain and an extracellular domain that binds to EGF. Ligand binding to the EGF receptor results in its dimerization, autophosphorylation and activation. Once activated, the EGF receptor transmits intracellular signals via the phosphorylation of several proteins.

The activation of Ras by the EGF receptor is an important component in EGF signaling. The guanine nucleotide exchange factor SOS activates Ras, which in turn triggers the mitogenactivated protein (MAP) kinase pathway. MAP kinases phosphorylate transcription factors like activator protein 1 (AP-1; Fos-Jun dimer) and Elk-1, leading to cellular growth and development. The phosphorylation of Janus kinases (JAK) by EGFR results in the activation of Signal Transducer and Activator of Transcription proteins (STATs) which ultimately lead to cell growth and differentiation. Another key aspect of EGF signaling involves Phospholipase C-gamma 1 (PLCγ1), which cleaves PIP2 into IP3 and DAG. IP3 production results in endoplasmic reticulum calcium release while DAG promotes the activation of Protein Kinase C (PKC). PKC in turn phosphorylates and activates the transcription factor Elk-1 which leads to cellular proliferation. Mutations in EGFR affecting its expression or activity are known to be involved in cancers, making EGFR an important drug target.

This pathway highlights the important components of EGF signal transduction.

Highlights from the EGF Signaling Pathway


Gene Symbol Name Cellular Functions Disease Associations Subcellular Locations Upstream Regulators Binding Partners Downstream Interactors Antibodies Small Molecules
STAT3 signal transducer and activator of transcription 3 (acute-phase response factor) proliferation
apoptosis
expression in
transformation
differentiation
tumorigenesis
obesity
enterocolitis
Crohn’s Disease
hyperphagia
nucleus
cytoplasm
focal adhesions
nuclear foci
plasma membrane
IL6
IL10
IL2
IL21
Interferon Alpha
FOS
EGFR
PRKCD
DIRAS3
IL2RB
TERT
IL10
HIF1A
CDKN1A
SOCS3
SAB2500993, Anti-STAT3 antibody produced in goat  
EGFR epidermal growth factor receptor proliferation
apoptosis
migration
transformation survival
cancer
tumorigenesis
neoplasia
psoriasis
endometriosis
cell surface
plasma membrane
nucleus
cytoplasm
caveolae
EGF
TNF
CBL
lysophosphatidic acid
HBEGF
EGF
AXL
GRB2
CBL
SRC
Mapk
MAPK1
Akt
Erk1/2
MAPK3
E2156, Monoclonal Anti-EGF Receptor antibody produced in mouse Inhibitor: PZ0129, CP-380736
c-Raf v-raf-1 murine leukemia viral oncogene homolog 1 transformation
proliferation
apoptosis
cell cycle progression
cell death
transformation proliferation
apoptosis
cell cycle progression
cell death
cytoplasm
nucleus
perinuclear region
plasma membrane
filamentous network
EGF
TP53
JAK1
OSM
HRAS
HRAS
YWHAZ
MAP2K1
YWHAB
RB1
MAPK1
RB1
HMGA2
MAP2K1
Mapk
R2404, Monoclonal Anti-Raf-1/c-Raf antibody produced in mouse Inhibitor: G6416, GW5074
JNK1 mitogen-activated protein kinase 8 apoptosis
cell death
proliferation
survival
differentiation
tumorigenesis
hypertrophy
insulin resistance
cancer
heart failure
nucleus
cytoplasm
focal adhesions
plasma membrane
mitochondria
TNF
EGF
IL1B
EGFR
IGF1
JUN
MAPK8IP1
MAP2K4
MAP2K7
THRB
CDKN1B
JUN
APP
AP-1
MAP3K11
SAB4200176, Monoclonal Anti-JNK antibody produced in mouse Inhibitor: S5567, SP600125
c-Jun jun proto-oncogene apoptosis
proliferation
transformation
expression in cell death
tumorigenesis
cancer
neoplasia
Alzheimer’s Disease
dedifferentiation
nucleus
cytoplasm
perinuclear region
Golgi apparatus
apical processes
TNF
IL1B
beta-estradiol
TGFB1
lipopolysaccharide
FOS
PTGS2
MAPK8
TAF1
ATF2
HIF1A
SPP1
IL6
IL8
ESR2
SAB4300305, Anti-JUN (Ab-91) antibody produced in rabbit  
PKCα protein kinase C, alpha apoptosis
proliferation
activation in
migration
phosphorylation in
neurodegenerative disease
diabetes
rheumatoid arthritis
malignant neoplasm
cardiomyopathy
cytoplasm nucleus
plasma membrane
principal piece
cytoskeleton
phosphatidylserine
EGF
beta-estradiol
15(S)-HETE
D-glucose
ITGB1
AKAP12
EGFR
CAV1
SELL
Erk1/2
APP
PDE3A
MAPK1
IGF2
WH0005578M1, Monoclonal Anti-PRKCA antibody produced in mouse Inhibitor: K1639, K-252a
STAT1 signal transducer and activator of transcription 1, 91kDa apoptosis
expression in
proliferation
response
differentiation
infection
tumorigenesis
pneumonia
cancer
fibrosis
nucleus
cytoplasm
mitochondria
neuromuscular
junctions
IFNG
Interferon Alpha
IFNA2
IL6
IFNB1
EIF2AK2
IFNGR1
FOS
STAT2
PIN1
IRF1
CDKN1A
IRF7
CASP1
CD40
SAB4300326, Anti-STAT1 (Ab-701) antibody produced in rabbit  
EGF epidermal growth factor proliferation
migration
apoptosis
growth
activation in
Alzheimer’s Disease
diabetes mellitus
polycystic kidney disease
schizophrenia
cancer
apical membrane
basolateral membrane
cell surface
Golgi apparatus
clathrin-coated
vesicles
ERBB2
ERBB3
ADAM10
CHUK
PI4KA
EGFR
ERBB3
ERBB2
PIK3R2
TAT
EGFR
MAPK1
MAPK3
FLT1
Erk1/2
E2520, Monoclonal Anti-Epidermal Growth Factor antibody produced in mouse Inhibitor: S2671, Suramin sodium salt
GRB2 growth factor receptor-bound protein 2 growth
proliferation
differentiation
signaling
transformation
Crohn’s disease
leiomyomatosis
cardiac fibrosis
hypertrophy
uterine cancer
centrosome
cytosol
perinuclear region
plasma membrane
axons
F2
EGF
Bcr
IGF1
SHC1
SHC1
CBL
SOS1
EGFR
GAB1
MAPK3
EGFR
ERBB2
RAF1
CBL
SAB2500491, Anti-GRB2 antibody produced in goat  
MEK1 mitogen-activated protein kinase kinase1 apoptosis
proliferation
transformation
differentiation
migration
tumorigenesis
neoplasia
hypertrophy
cardiofaciocutaneous
syndrome
hyperalgesia
cytoplasm
midbody
nucleus
centrosome
mitotic spindle
EGF
LEF
RAF1v RAC1
TNF
MAPK1
RAF1
MAPK3
PEBP4
KSR1
MLANA
MAPK1
DCT
SILV
TYRP1
SAB4502408, Anti-MEK1 antibody produced in rabbit Inhibitor: P215, PD 98,059
hRas v-Ha-ras Harvey rat sarcoma viral oncogene homolog transformation
proliferation
growth
apoptosis
senescence
tumorigenesis
cancer
neoplasia
papillomatosis
neurodegeneration
nucleus
plasma membrane
Golgi apparatus
cytoplasm
lamellipodia
Cd3
CD28
AXIN1
FTase
IL6
RAF1
RALGDS
RIN1
Blnk
Raf
reactive oxygen
species
CDKN1A
MAPK1
Erk1/2
Mapk
SAB4501441, Anti-RASH, N-Terminal antibody produced in rabbit Antagonist: E7781, Erastin
c-Fos FBJ murine osteosarcoma viral oncogene homolog transformation
apoptosis
proliferation
expression in
growth
cancer
rheumatoid arthritis
endometriosis
neoplasia
seizures
nucleus
cytoplasm
perinuclear region
Golgi apparatus
cell periphery
beta-estradiol
TNF
IL1B
EGF
ESR2
JUN
STAT3
PTGS2
SRF
IL8
IL6
CSF2
ESR2
IL8
CFLAR
SAB2104185, Anti-FOS antibody produced in rabbit  

EGF Signaling

Find additional annotations and products for this pathway at sigma.com/EGFSig.

Materials

     

References

  1. Corbalan-Garcia S, Margarit SM, Galron D, Yang SS, Bar-Sagi D. Regulation of Sos activity by intramolecular interactions. Mol Cell Biol. 1998 Feb;18(2):880–6.
  2. Russell M, Lange-Carter CA, Johnson GL. Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1). J Biol Chem. 1995 May;270(20):11757–60.
  3. Ackerman P, Glover CV, Osheroff N. Stimulation of casein kinase II by epidermal growth factor: relationship between the physiological activity of the kinase and the phosphorylation state of its beta subunit. Proc Natl Acad Sci U S A. 1990 Jan;87(2):821–5.
  4. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK. EGFR-induced cell migration is mediated predominantly by the JAKSTAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol. 2004 Dec;287(6):G1227–37.
  5. Baker SJ, Kerppola TK, Luk D, Vandenberg MT, Marshak DR, Curran T, Abate C. Jun is phosphorylated by several protein kinases at the same sites that are modified in serum-stimulated fibroblasts. Mol Cell Biol. 1992 Oct;12(10):4694–705.
  6. Takekawa M, Tatebayashi K, Saito H. Conserved Docking Site Is Essential for Activation of Mammalian MAP Kinase Kinases by Specific MAP Kinase Kinase Kinases. Mol Cell. 2005 Apr;18(3):295–306.
  7. Chong MP, Barritt GJ, Crouch MF. Insulin potentiates EGFR activation and signaling in fibroblasts. Biochem Biophys Res Commun. 2004 Sept;322(2):535–41.
  8. Krug A, Schuster C, Gassner B, Freudinger R, Mildenberger S, Troppmair J, Gekle M. Human EGF receptor 1 (HER1) expression renders CHO cells sensitive to alternative aldosterone signaling. J Biol Chem. 2002 Nov;277(48):45892–7.
  9. Lim CP, Cao X. Serine phosphorylation and negative regulation of Stat3 by JNK. J Biol Chem. 1999 Oct;274(43):31055–61.
  10. Diakonova M, Payrastre B, van Velzen AG, Hage WJ, van Bergen en Henegouwen PM, Boonstra J, Cremers FF, Humbel BM. Epidermal growth factor induces rapid and transient association of phospholipase C-gamma 1 with EGF-receptor and filamentous actin at membrane ruffes of A431 cells. J Cell Sci. 1995 Jun;108(Pt 6):2499–509.
  11. Eldar H, Zisman Y, Ullrich A, Livneh E. Overexpression of protein kinase C alpha-subtype in Swiss/3T3 fibroblasts causes loss of both high and low affinity receptor numbers for epidermal growth factor. J Biol Chem. 1990 Aug;265(22):13290–6.
  12. Weston CR, Wong A, Hall JP, Goad ME, Flavell RA, Davis RJ. The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis. Proc Natl Acad Sci U S A. 2004 Sep;101(39):14114–9.
  13. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem. 1990 May;265(14):7709–12.
  14. Hu Y, Bowtell DD. Sos1 rapidly associates with Grb2 and is hypophosphorylated when complexed with the EGF receptor after EGF stimulation. Oncogene. 1996 May;12(9):1865–72.
  15. Ueno H, Sasaki K, Miyagawa K, Honda H, Mitani K, Yazaki Y, Hirai H. Antisense repression of protooncogene c-Cbl enhances activation of the JAKSTAT pathway but not the ras pathway in epidermal growth factor receptor signaling. J Biol Chem. 1997 Mar;272(13):8739-43.
  16. Cummins AB, Palmer C, Mossman BT, Taatjes DJ. Persistent Localization of Activated Extracellular Signal-Regulated Kinases (ERK1/2) Is Epithelial Cell- Specific in an Inhalation Model of Asbestosis. Am J Pathol. 2003 Mar;162(3):713–20.
  17. Yoshikawa S, Tanimura T, Miyawaki A, Nakamura M, Yuzaki M, Furuichi T, Mikoshiba K. Molecular cloning and characterization of the inositol 1,4,5-trisphosphate receptor in Drosophila melanogaster. J Biol Chem. 1992 Aug;267(23):16613–9.
  18. Mahimainathan L, Ghosh-Choudhury N, Venkatesan BA, Danda RS, Choudhury GG. EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fos and p27Kip1. Am J Physiol Renal Physiol. 2005 Jul;289(1):F72–82.
  19. Xia Y, Makris C, Su B, Li E, Yang J, Nemerow GR, Karin M. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5243–8.
  20. Chen DB, Davis JS. Epidermal growth factor induces c-fos and c-jun mRNA via Raf-1/MEK1/ERKdependent and -independent pathways in bovine luteal cells. Mol Cell Endocrinol. 2003 Feb;200(1– 2):141–54.

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