Signal Transduction and Cancer

Lecture I: Growth Factors and ReceptorsOutline:A) What is Signal Transduction?B) What are Growth Factors?C) How do they contribute to normal ST?D) How is this ST deregulated in Cancer?

Lecture I: Growth Factors and ReceptorsWhat is Signal Transduction?

Signal Transduction is the process by which a cell converts an extracellular signal into a response.

Involved in:Cell-cell communication

Cell’s response to environment

Intracellular homeostatsis- internal communication

Generic Signalling Pathway

Signal

Receptor (sensor)

Transduction Cascade

Targets

Response

Altered Metabolism

MetabolicEnzyme

Gene Regulator Cytoskeletal Protein

Altered Gene

Expression

Altered Cell Shape or Motility

Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.

Components of SignallingWhat can be the Signal?External message to the cell

• Peptides / Proteins- Growth Factors• Amino acid derivatives - epinephrine, histamine• Other small biomolecules - ATP• Steroids, prostaglandins• Gases - Nitric Oxide (NO)• Photons• Damaged DNA• Odorants, tastants

Signal = LIGANDLigand- A molecule that binds to a specific site on another molecule, usually a protein, ie receptor

Components of SignallingWhat are Receptors?Sensors, what the signal/ligand binds to initiate ST

Cell surface

Intracellular

Hydrophillic LigandCell-Surface Receptor

Plasma membrane

Hydrophobic Ligand

Carrier Protein

IntracellularReceptor

Nucleus

Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.

Cell Surface Receptor Types:

1) Ligand-gated ion channel

Cell Surface Receptor Types:

2) G-Protein Coupled Receptor

Cell Surface Receptor Types:

3) Enzyme-linked Receptor eg Growth Factor Receptors

Growth FactorsLigands which bind enzyme linked receptorsSignal diverse cellular responses including:ProliferationDifferentiationGrowthSurvival Angiogenesis

Can signal to multiple cell types or be specific

Factor Principal Source

Primary Activity Comments

PDGF platelets, endothelial cells, placenta

promotes proliferation of connective tissue, glial and smooth muscle cells

two different protein chains form 3 distinct dimer forms; AA, AB and BB

EGF submaxillary gland, Brunners gland

promotes proliferation of mesenchymal, glial and epithelial cells

 

TGF- common in transformed cells

may be important for normal wound healing

related to EGF

FGF wide range of cells; protein is associated with the ECM

promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos

at least 19 family members, 4 distinct receptors

NGF   promotes neurite outgrowth and neural cell survival

several related proteins first identified as proto-oncogenes; trkA (trackA), trkB, trkC

Erythropoietin kidney promotes proliferation and differentiation of erythrocytes

 

TGF- activated TH1 cells (T-helper) and natural killer (NK) cells

anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation

at least 100 different family members

IGF-I primarily liver promotes proliferation of many cell types

related to IGF-II and proinsulin, also called Somatomedin C

IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin

related to IGF-I and proinsulin

Growth Factors

Growth Factor Receptors

Most growth factors bind Receptor Tyrosine Kinases

Characteristics of the Common Classes ofRTKs

Class Examples Structural Features of Class

IEGF receptor,NEU/HER2, HER3

cysteine-rich sequences

IIinsulin receptor,IGF-1 receptor

cysteine-rich sequences; characterized bydisulfide-linked heterotetramers

IIIPDGF receptors,c-Kit

contain 5 immunoglobulin-like domains;contain the kinase insert

IV FGF receptorscontain 3 immunoglobulin-like domains aswell as the kinase insert; acidic domain

V

vascularendothelial cellgrowth factor(VEGF) receptor

contain 7 immunoglobulin-like domains aswell as the kinase insert domain

VI

hepatocyte growthfactor (HGF) andscatter factor (SC)receptors

heterodimeric like the class II receptorsexcept that one of the two protein subunitsis completely extracellular. The HGFreceptor is a proto-oncogene that wasoriginally identified as the Met oncogene

VII

neurotrophinreceptor family(trkA, trkB, trkC)and NGF receptor

contain no or few cysteine-rich domains;NGFR has leucine rich domain

Growth Factor Receptor Activation IRTK RS/TK

Growth Factor Receptor Activation II

Growth signal autonomy,Insensitivity to anti-growth signals,Resistance to apoptosis:Uncouple cell’s growth program from signals in the environment.

Growth factors in normal cells serveas environmental signals.

Growth Factor ST and Cancer

Growth factors regulate growth, proliferation, and survival.These are all deregulated in cancer.

Hanahan and Weinberg, (2000) Hallmarks of Cancer, Cell (100) 57

Growth factors with Oncogenic PotentialPDGF, originally shown to regulate proliferation, was also shown to have homology to v-sis, the simian sarcoma virus. Other viral oncogenes encoded protein products that were growth factors that often overexpressed in cancer such as TGF-a. Autocrine signalling leads to deregulated growth. PDGF family Neurotrophins

A chain NGFB chain (c-sis) BDNF

FGF Family NT3acidic FGF Cytokines (Hematopoietic)basic FGF IL-2

EGF Family IL-3EGF M-CSFTGF-a GM-CSF

GF Receptors with Oncogenic PotentialEGFR, kinase activity stimulated by EGF-1 and TGF-a involved incell growth and differentiation, was linked via sequence homology to a known avian erythroblastosis virus onocgene, v-erbB. Since then, many oncogenes have been shown to encode for GFRs. EGFR family Insulin Receptor family

erbB1 (c-erbB) IGF-1 (c-ros)erbB2 (neu) Neurotrophins

FGF Family NGFR (trk) FGFR-1(fig) BDNFR (trk-B)FGFR-2(K-sam) NT3 R (trk-C)

PDGFR FamilyCSF-1R (c-fms)SLF R (c-kit)

Induction of cancer by alternations in several types of proteins involved in cell growth control

Signal Transduction and Cancer

Lecture II: Intracellular SignallingOutline:A) What are some signalling pathways?B) What are their cell biological outputs?C) How do these result in the cancer phenotype?D) How can we exploit signalling pathways for therapy?

Generic Signal Transduction

RTK Signal Transduction

Signal TransductionDownstream effectors

Protein Signaling Modules (Domains)

SH2 and PTB bind to tyrosine phosphorylated sitesSH3 and WW bind to proline-rich sequencesPDZ domains bind to hydrophobic residues at the C-termini of target proteinsPH domains bind to different phosphoinositidesFYVE domains specifically bind to Pdtlns(3)P (phosphatidylinositol 3-phosphate)

Mechanisms for Activation of Signaling Proteins by RTKs

Activation by membrane translocation

Activation by a conformational change

Activation by tyrosine phosphorylation

Mechanisms for Attenuation & Termination of RTK Activation

1) Ligand antagonists2) Receptor antagonists3) Phosphorylation and dephosphorylation4) Receptor endocytosis5) Receptor degradation by the ubiquitin-proteosome pathway

Activation of MAPK Pathways by Multiple Signals

Growth, differentiation, inflammation, apoptosis -> tumorigenesis

Overview of MAPK Signaling Pathways

The MAPK Pathway Activated by RTK

P

RTK ST- PI3K pathway

Proto-oncogenes that Encode for Signalling Proteins

Serine/Threonine Kinasesc-raf familyakt

Non-receptor Tyrosine Kinasessrcabl

Receptor associated binding proteinsc-ras family

Ras recruits Raf to the membrane

The prototypic TK oncogene is bcr/abl. The bcr/abl fusiononcogene i s formed when the c-abl TK gene onchromosome 9 is translocated to chromosome 22 and fusedwith part of the bcr gene on that chromosome. The resultinghybrid chromosome, the Philadelphia chromosome, encodesa new protein called Bcr/Abl. New protein has increasedkinase activity and drives proliferation causingtransformation. Charatceristic of CML a nd some forms ofALL.

C-abl: Tyrosine Kinase activation by Translocation

ST intermediates can be targets for anti-cancer drugs

Kinases:Raf

ST intermediates can be targets for anti-cancer drugs

Kinases:Bcr-Abl

Growth Factor Receptors can be drug targets