Growth Factors

Question 1

Growth Factor Signaling

Answer 1

Endocrine, paracrine, autocrine,
Cells need a way to monitor their environment and respond appropriately
Growth factors are typically small peptides or proteins
Secreted by multiple cell types – “how cells talk to each other or themselves”
Bind to extracellular receptors on the cell surface
Detection of growth factors results in a transfer of signal to the intracellular side.
Transmission of signal to effector molecules results in changes to downstream signaling pathway proteins, typically through phosphorylation (by kinases) or dephosphorylation (by
phosphatases)
Ultimately triggers a specific set of cellular responses, such as gene program activation

Question 2

Growth Receptor Activation

Answer 2

Often begins with Autophosphorylation: Receptor phosphorylates itself
Transphosphorylation: Receptor phosphorylates its binding partner

Some receptors have no catalytic domain, ie, adhesion receptors such as Integrins
Receptors such as Integrins function to connect the cytoplasm with the stromal microenvironment and Extracellular Matrix(ECM)

G-protein coupled receptors (GPCRs):
Largest and most diverse group of receptors
Can recognize lipids, sugars, peptides, proteins and light
Seven transmembrane domains
Also do not have a catalytic domain

Question 3

Catalytic Growth Receptors

Answer 3

Receptor Tyrosine Kinases (RTKs) phosphorylate Tyrosines
Homodimer: 2 identical receptors cluster together to induce signaling
Heterodimer: 2 different receptors cluster together to induce signaling
Growth factors induced receptor clustering is determined by:
High affinity binding
Ligand-mediated receptor crosslinking
EGFR: Ligand Binding Stabilizes Formation of Activated Receptor:
Without Ligand : Inactive Monomers, Inactive Dimer, Active Dimer are in Equilibrium
With Ligand : Ligand binding stabilizes active dimer and promotes phosphorylation and RTK activation.
Receptor activation by homodimer or heterodimer:
Requires the ability to crosslink receptors.
Receptor Serine/Threonine Kinases (RSTKs) phosphorylate Serines and/or Threonine

Question 4

Growth Factors in Cancer

Answer 4

Growth Factors in Cancer : Aberrant Autocrine Loops

• Overexpression of Hedgehog(Hh) ligands can result in both autocrine and paracrine signals to promote tumor progression
• Paracrine Growth Factors that contribute to Tumor Progression

Question 5

HER2 Signalling

Answer 5

Activation of MAPK pathway is a potent driver of cancer
RAS gene mutations are common occurrences in cancer
RAS mutants are hard to treat as they are intrinsically active
Activation of Ras is critical to the cancer functions of receptors such as HER2

• Activation of RTKs results in recruitment of PI3K which recruits AKT to the plasma membrane through PIP2 phosphorylation into PIP3 that recruits AKT.
• AKT is then phosphorylated by PDK1.
  AKT is a Serine/Threonine kinase
• Targets both cytoplasmic and nuclear proteins
• Activates proliferative and growth signals
• Inhibits cell cycle inhibitors and apoptotic responses = Enhanced cancer cell survival

Question 6

Death Receptor

Answer 6

Death receptor : Induce Apoptosis
FADD = Fas-Associated protein with Death Domain
DD = death domain, another protein interaction motif
DED = death effector domain
DD and DED form dimers

Question 7

Approaches to Targeted Therapy

Answer 7

Approaches to Targeted Therapy:
1. Blocking Antibodies
2. Soluble Receptors
3. Inhibitors of receptor kinases or chaperone proteins (receptor stability)
4. Inhibit downstream signaling pathway
5. Epigenetic modulators
6. General cancer therapy – not targeted