chapter 5: growth factors, receptors, and cancer
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Chapter 5:
Growth Factors, Receptors, and Cancer
Spatial and temporal control of cell growth and differentiation via communication between individual cells are pivotal for maintaining functional and structural integrity of tissues and organs
Effect of growth factors on cell proliferation and migration
Experimental clues for cell-to-cell signaling via growth factors from studies for the tyrosine kinase activity of v-Src
Pleiotropic actions and substrate specificity of protein kinases
[1] Receptor tyrosine kinases (RTKs)
Structures of RTKs
Alterations in structures and expression of RTKs make them function as oncogenes
Transphosphorylation underlies the operation of RTKs
Human A431 epidermoid carcinoma cells
206 human glioblastomas
Alternative mechanisms of growth factor-induced receptor dimerization
Constitutive dimerization of RTKs by gene fusion
Multiple structural alteration affecting Kit firing
[2] Cytokine receptor noncovalently interacting with tyrosine kinases
[3] Receptors with serine/threonine kinase activity
[4] Notch receptor of which activation depends on proteolytic cleavage
[5] Patched-smoothened signaling system (Hedgehog pathway)
[6] Canonical Wnt signaling via frizzled receptors
[6] Non-canonical Wnt signaling via frizzled receptors: G-protein-coupled receptor (GPCR)
[7] Nuclear receptors activated by lipophilic ligands
[8] Receptors sensing association between the cell and the extracellular matrix (ECM)
Integrins
Integrin tethering to the ECM and cytoskeleton
Suppressed mammary tumorigenesis in the absence of 1 integrin
Activation of Ras, a small-GTP binding protein, by RTKs
Grb2Grb2
SOSSOS Ras*Ras*
Raf*Raf*
MEKMEK
ERK1/2ERK1/2
RSKRSK
MycMyc
Elk-1Elk-1
TranslationTranscription
EGFR mutaion: NSCLC (10%) Glioblastoma (20%)
EGFR overexpression: Colorectal cancer (22-77%) Pancreatic cancer (30-50%) Lung cancer (40-80%) Non-small cell lung cancer (14-91%)
Ras mutation: Papillary thyroid cancer (90%) Pancreatic cancer (60%) Colon cancer (50%) Non-small cell lung cancer (30%)
B-raf mutation: Melanoma (70%) Papillary thyroid cancer (50%) Colon cancer (10%)
Survival / Proliferation / Suppression of apoptosis
Imatinib Farnesyl transferase
SB590885PLX4720
XL281RAF256
SorafenibPLX4032
XL518CI-1040PD035091AZD6244GSK1120212
Ras/Raf/MAPK signaling cascade activated in human cancers and anti-cancer drugs, targeting the pathway, currently in development. Asterisk indicates mutations found in human cancers.
Alternative mechanisms of transformation by Ras
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