EGF Signaling: Tracking the path of Cancer
The epidermal growth factor (EGF) family is a group of structurally related proteins that regulate cell proliferation, migration and differentiation through tyrosine kinase receptors on target cells. EGF receptors have a cytoplasmic tyrosine kinase domain, a transmembrane domain, and an extracellular domain that binds to EGF. Binding of the ligand to the EGF receptor results in dimerization, autophosphorylation, and activation. Once activated, EGF receptors transmit intracellular signals through the phosphorylation of several proteins.
Activation of Ras by EGF receptors is an important component of EGF signaling. The guanine nucleotide exchange factor SOS activates Ras, which in turn triggers the mitogen-activated protein (MAP) kinase pathway. MAP kinases phosphorylate transcription factors such as activator protein 1 (AP-1; Fos-Jun dimer) and Elk-1, leading to cell growth and development. Phosphorylation of Janus kinase (JAK) by EGFR leads to activation of transcriptional protein signal transducers and activators (STATs), ultimately leading to cell growth and differentiation. Another key aspect of EGF signaling involves the phospholipase c-γ1 (PLCγ1), which cleaves PIP2 into IP3 and DAG. IP3 production leads to ER calcium release, whereas DAG promotes protein kinase C (PKC) activation. PKC in turn phosphorylates and activates the transcription factor Elk-1, leading to cell proliferation. Mutations in EGFR are known to affect its expression or activity, making EGFR an important drug target.
This pathway highlights an important component of EGF signaling.
Emphasis on epidermal growth factor 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 | Anti-STAT3 antibody produced in goat |
|
EGFR | epidermal growth factor receptor | proliferation | cancer | cell surface | EGF | EGF | Mapk | Monoclonal Anti-EGF Receptor antibody produced in mouse | Inhibitor: CP-380736 |
c-Raf | v-raf-1 murine leukemia viral oncogene homolog 1 | transformation | transformation proliferation | cytoplasm | EGF | HRAS | MAPK1 | Monoclonal Anti-Raf-1/c-Raf antibody produced in mouse | GW5074 |
JNK1 | mitogen-activated protein kinase 8 | apoptosis | tumorigenesis | nucleus | TNF | JUN | CDKN1B | Monoclonal Anti-JNK antibody produced in mouse | Inhibitor: SP600125 |
c-Jun | jun proto-oncogene | apoptosis | tumorigenesis | nucleus
| TNF | FOS
| HIF1A | Anti-JUN(Ab-91) antibody produced in rabbit |
|
PKCα | protein kinase C, alpha | apoptosis | neurodegenerative disease | cytoplasm nucleus | phosphatidylserine | ITGB1 | Erk1/2 | Monoclonal Anti-PRKCA antibody produced in mouse | Inhibitor: K-252a |
STAT1 | signal transducer and activator of transcription 1, 91kDa | apoptosis | infection | nucleus | IFNG | EIF2AK2 | IRF1 | Anti-STAT1(Ab-701) antibody produced in rabbit |
|
EGF | epidermal growth factor | proliferation | Alzheimer’s Disease | apical membrane | ERBB2 | EGFR | EGFR | Monoclonal Anti-Epidermal Growth Factor antibody produced in mouse | Inhibitor: Suramin sodium salt |
GRB2 | growth factor receptor-bound protein 2 | growth | Crohn’s disease | centrosome | F2
| SHC1
| MAPK3
| Anti-GRB2 antibody produced in goat |
|
MEK1 | mitogen-activated protein kinase kinase1 | apoptosis | tumorigenesis | cytoplasm | EGF | MAPK1 | MLANA | Anti-MEK1 antibody produced in rabbit | Inhibitor: PD98,059 |
hRas | v-Ha-ras Harvey rat sarcoma viral oncogene homolog | transformation | tumorigenesis | nucleus | Cd3 | RAF1 | reactive oxygen | Anti-RASH，N-Terminal antibody produced in rabbit | Antagonist: Erastin |
c-Fos | FBJ murine osteosarcoma viral oncogene homolog | transformation | cancer | nucleus | beta-estradiol | JUN | IL6 | Anti-FOS antibody produced in rabbit |
References
1. Corbalan-Garcia S, Margarit SM, Galron D, Yang S, Bar-Sagi D. 1998. Regulation of Sos Activity by Intramolecular Interactions. Mol. Cell. Biol.. 18(2):880-886. https://doi.org/10.1128/mcb.18.2.880
2. Russell M, Lange-Carter CA, Johnson GL. 1995. Direct Interaction between Ras and the Kinase Domain of Mitogen-activated Protein Kinase Kinase Kinase (MEKK1). Journal of Biological Chemistry. 270(20):11757-11760. https://doi.org/10.1074/jbc.270.20.11757
3. Ackerman P, Glover CV, Osheroff N. 1990. 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.. Proceedings of the National Academy of Sciences. 87(2):821-825. https://doi.org/10.1073/pnas.87.2.821
4. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK. 2004. EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. American Journal of Physiology-Gastrointestinal and Liver Physiology. 287(6):G1227-G1237. https://doi.org/10.1152/ajpgi.00253.2004
5. Baker SJ, Kerppola TK, Luk D, Vandenberg MT, Marshak DR, Curran T, Abate C. 1992. Jun is phosphorylated by several protein kinases at the same sites that are modified in serum-stimulated fibroblasts.. Mol. Cell. Biol.. 12(10):4694-4705. https://doi.org/10.1128/mcb.12.10.4694
6. Takekawa M, Tatebayashi K, Saito H. 2005. Conserved Docking Site Is Essential for Activation of Mammalian MAP Kinase Kinases by Specific MAP Kinase Kinase Kinases. Molecular Cell. 18(3):295-306. https://doi.org/10.1016/j.molcel.2005.04.001
7. Chong M, Barritt G, Crouch M. 2004. Insulin potentiates EGFR activation and signaling in fibroblasts. Biochemical and Biophysical Research Communications. 322(2):535-541. https://doi.org/10.1016/j.bbrc.2004.07.150
8. Krug AW, Schuster C, Gassner B, Freudinger R, Mildenberger S, Troppmair J, Gekle M. 2002. Human Epidermal Growth Factor Receptor-1 Expression Renders Chinese Hamster Ovary Cells Sensitive to Alternative Aldosterone Signaling. Journal of Biological Chemistry. 277(48):45892-45897. https://doi.org/10.1074/jbc.m208851200
9. Lim CP, Cao X. 1999. Serine Phosphorylation and Negative Regulation of Stat3 by JNK. Journal of Biological Chemistry. 274(43):31055-31061. https://doi.org/10.1074/jbc.274.43.31055
10. Diakonova M, Payrastre B, van Velzen AG, Hage W, van Bergen en Henegouwen PM, Boonstra J, Cremers F, Humbel B. 1995. 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..(108):2499–2509.
11. Eldar H, Zisman Y, Ullrich A, Livneh E. 1990. 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.. Journal of Biological Chemistry. 265(22):13290-13296. https://doi.org/10.1016/s0021-9258(19)38297-3
12. Weston CR, Wong A, Hall JP, Goad MEP, Flavell RA, Davis RJ. 2004. The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis. Proceedings of the National Academy of Sciences. 101(39):14114-14119. https://doi.org/10.1073/pnas.0406061101
13. Carpenter G, Cohen S. 1990. Epidermal growth factor.. Journal of Biological Chemistry. 265(14):7709-7712. https://doi.org/10.1016/s0021-9258(19)38983-5
14. Hu, Bowtell D. 1996. Sos1 rapidly associates with Grb2 and is hypophosphorylated when complexed with the EGF receptor after EGF stimulation. Oncogene.. 12(9):1865–72.
15. Ueno H, Sasaki K, Miyagawa K, Honda H, Mitani K, Yazaki Y, Hirai H. 1997. Antisense Repression of Proto-oncogene c-Cbl Enhances Activation of the JAK-STAT Pathway but Not the Ras Pathway in Epidermal Growth Factor Receptor Signaling. Journal of Biological Chemistry. 272(13):8739-8743. https://doi.org/10.1074/jbc.272.13.8739
16. Cummins AB, Palmer C, Mossman BT, Taatjes DJ. 2003. Persistent Localization of Activated Extracellular Signal-Regulated Kinases (ERK1/2) Is Epithelial Cell-Specific in an Inhalation Model of Asbestosis. The American Journal of Pathology. 162(3):713-720. https://doi.org/10.1016/s0002-9440(10)63867-9
17. Yoshikawa S, Tanimura T, Miyawaki A, Nakamura M, Yuzaki M, Furuichi T, Mikoshiba K. 1992. Molecular cloning and characterization of the inositol 1,4,5-trisphosphate receptor in Drosophila melanogaster.. Journal of Biological Chemistry. 267(23):16613-16619. https://doi.org/10.1016/s0021-9258(18)42047-9
18. Mahimainathan L, Ghosh-Choudhury N, Venkatesan BA, Danda RS, Choudhury GG. 2005. EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fos and p27Kip1. American Journal of Physiology-Renal Physiology. 289(1):F72-F82. https://doi.org/10.1152/ajprenal.00277.2004
19. Xia Y, Makris C, Su B, Li E, Yang J, Nemerow GR, Karin M. 2000. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. Proceedings of the National Academy of Sciences. 97(10):5243-5248. https://doi.org/10.1073/pnas.97.10.5243
20. Chen D, Davis JS. 2003. Epidermal growth factor induces c-fos and c-jun mRNA via Raf-1/MEK1/ERK-dependent and -independent pathways in bovine luteal cells. Molecular and Cellular Endocrinology. 200(1-2):141-154. https://doi.org/10.1016/s0303-7207(02)00379-9