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

e.g. Wound healing

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