H4 Growth factor signaling and oncogenes
- Tyrosine kinases phosphorylate tyrosine amino acids (OH group) in
target proteins conformational change of protein
4.1 Epidermal growth factor (EGF) signaling: an important
paradigm
- EGFR = EGF tyrosine kinase receptor
o ErbB1/HER1
o ErbB2/HER2 binds no ligands, but is a co-receptor
o ErbB3/HER3 weak activity
o ErbB4/HER4
- Extracellular ligand-binding domain
- Single transmembrane domain
- Cytoplasmic protein tyrosine kinase domain
Figure 4.2 The signal transduction pathway of EGF: growth factor
binding, receptor dimerization, autophosphorylation, activation of
intracellular transducers, a serine/threonine kinase cascade, and
transcription factors, and regulation
of gene expression.
Figure 4.3 EGF receptor dimerization. Growth factor binding
conformational change unmasks dimerization domain (gray triangles)
, required for receptor dimerization. ATP and substrate of the catalytic
kinase domain access Autophosphorylation: 1 kinase domain of the
receptor phosphorylates another receptor
Inactivating EGFR:
- Inhibitory phosphate
- Dephosphorylation
- Binding of negative regulators
- Receptor endocytosis and degradation
Translocation of specific proteins to the membrane
The phosphorylated tyrosines create binding sites for proteins that contain
SH2 domains
- SH2 domains of Grb2 bind to phosphorylated EGFR
- SH3 domains of Grb2 bind to proline-rich and hydrophobic
sequences on other proteins (SOS)
SOS activates RAS
Ras activation
- N-RAS, H-RAS, K-RAS
- Inactive when bound to GDP
- Active when bound to GTP
SOS = Guanine nucleotide exchange factors help RAS to release
GDP, allowing abundant GTP to bind
GTPase-activating proteins (GAPs) stimulate the hydrolysis of GTP back
to GDP
Farnesylation = attaches a lipid to RAS anchors RAS at the membrane
Raf activation
Ras binds and activates (not by phosphorylating!) Raf
Raf (serine/threonine kinase) phosphorylates MEK
MAP kinase cascade
MEK phosphorylates MAPKs (ERKs)
In the nucleus: MAPKs phosphorylates transcription factors activate
tf
Parallel MAP kinase pathways:
- MAPK
- JNK, activated by environmental stress signals
- Tyrosine kinases phosphorylate tyrosine amino acids (OH group) in
target proteins conformational change of protein
4.1 Epidermal growth factor (EGF) signaling: an important
paradigm
- EGFR = EGF tyrosine kinase receptor
o ErbB1/HER1
o ErbB2/HER2 binds no ligands, but is a co-receptor
o ErbB3/HER3 weak activity
o ErbB4/HER4
- Extracellular ligand-binding domain
- Single transmembrane domain
- Cytoplasmic protein tyrosine kinase domain
Figure 4.2 The signal transduction pathway of EGF: growth factor
binding, receptor dimerization, autophosphorylation, activation of
intracellular transducers, a serine/threonine kinase cascade, and
transcription factors, and regulation
of gene expression.
Figure 4.3 EGF receptor dimerization. Growth factor binding
conformational change unmasks dimerization domain (gray triangles)
, required for receptor dimerization. ATP and substrate of the catalytic
kinase domain access Autophosphorylation: 1 kinase domain of the
receptor phosphorylates another receptor
Inactivating EGFR:
- Inhibitory phosphate
- Dephosphorylation
- Binding of negative regulators
- Receptor endocytosis and degradation
Translocation of specific proteins to the membrane
The phosphorylated tyrosines create binding sites for proteins that contain
SH2 domains
- SH2 domains of Grb2 bind to phosphorylated EGFR
- SH3 domains of Grb2 bind to proline-rich and hydrophobic
sequences on other proteins (SOS)
SOS activates RAS
Ras activation
- N-RAS, H-RAS, K-RAS
- Inactive when bound to GDP
- Active when bound to GTP
SOS = Guanine nucleotide exchange factors help RAS to release
GDP, allowing abundant GTP to bind
GTPase-activating proteins (GAPs) stimulate the hydrolysis of GTP back
to GDP
Farnesylation = attaches a lipid to RAS anchors RAS at the membrane
Raf activation
Ras binds and activates (not by phosphorylating!) Raf
Raf (serine/threonine kinase) phosphorylates MEK
MAP kinase cascade
MEK phosphorylates MAPKs (ERKs)
In the nucleus: MAPKs phosphorylates transcription factors activate
tf
Parallel MAP kinase pathways:
- MAPK
- JNK, activated by environmental stress signals
