Cancer Signaling Pathways

Question 1

Receptor Tyrosine Kinase Structure and Function

Answer 1

• gene family that binds growth factors and cytokines
• have ability to phosphorylate tyrosines on other proteins involved in controlling cell growth and differentiation
• ligand binding domain (extracellular N term)
• transmembrance domain
• phosphorylating domain (intracellular C term- cytosol)

ALMOST ALL MONOMERS

Question 2

What happens when a receptor tyrosine kinase is bound by ligand?

Answer 2

1- dimerization
2- autophosphorylation (self) or cross phosphorylation (other monomer)
3- phosphorylation leads to…inc receptor kinase activity and docking of other specific proteins

Question 3

What kinds of proteins to ligand-bound RTKs attract?

What is their function?

Answer 3

• SPECIFIC proteins w/ SH2 domains that recognize phosphotyrosine site (some also contain a second SH3 site)
• Recruit SH2 proteins to plasma membrane, have docking sites for association w/ other proteins, promotes their phosphorylation, stim associated enzyme activity (if present) Activation of downstream paths

Question 4

Phospholipase Path

Answer 4

1-PLC-gamma is a SH2 domain protein and is recruited to plasma membrane by binding its RTK
2-Phosphorylated once bound
3- Stim it to hydrolyze plasma membrane phospholipid PIP2 –> DAG and IP3
4- DAG then activated a variety of protein kinases and IP3 binds Ca++ channels in cell –> release of intracellular Ca++ stores
5- Ca++ goes on to activate select protein kinases and protein phosphatases

Question 5

MAPK Pathway

Answer 5

Mitogen Activation Protein Kinase

-Family of 4 proteins that are often mobilized by activation of RTKs

1- act RTK recruits Grb2/Sos to plasma membrane
2- Grb2/Sos interacts w/ Ras (monomeric G protein)
3- Ras-GTP is active form and activated MAPKKK
4- MAPKKK phosphorylates MAPKK
5- MAPKK phosphorylates MAPK

Question 6

How is Ras activated and deactivated?

Answer 6

• GDP = inactive form
• GTP = active form

GAPS inc rates of hydrolysis of bound GTP - deactivate
GEFs help stim loss of GDP and uptake of new GTP - activate

Question 7

Cytokines

Answer 7

-Proteins produced by immune system –> immune response

1- cytokines bind receptors
2- cytokine receptors stim intracellular NON-RECEPTOR tyrosine kinases

Question 8

Jak/STAT Pathway

Answer 8

STAT= signal transducers and activators of transcription
Jak= specific non receptor tyrosine kinase
1- Jak the cytokine receptor is stim
2- STAT proteins bind stim cytokine receptors (w/ their SH2 domains)
3- Jak phosphorylates STAT proteins
4- STAT proteins dimerize and translocate to nucleus where they stim transcription of target genes

Question 9

How are RTKs deactivated?

Answer 9

protein tyrosine phosphatase receptors (remove phosphates from phosphotyrosine residues)

**Endocytosis of ligand-receptor complexes –> internalized and degraded

Question 10

EGF Genes

Answer 10

-Family of proteins that bind 4 specific RTKs called HERs in humans (human epidermal growth factor receptors)

• DIVERSITY
• ea HER can bind mult ligands and ea ligand can bind mult HERs
• also recruits diverse # other proteins once bound
• dimerization b/n alike or diff HERs

Question 11

HER Receptors and Cancer

Answer 11

Mutations in HER receptors –> over expression or hyperactive response to growth factors –> cancer

Question 12

3 Drug Mechanisms Against RTKs

Answer 12

1- antibodies that bind extracellular domain of growth factor receptors (ex- HER2 - trastuzumab)

2- Inhibit kinase activity of RTK or non receptor tyrosine kinase w/ ATP analogies that compete for ATP-binding site

3- Immunotoxins to kill cells w/ RTKs