Cell signalling Flashcards
- Oncogenes and tumour suppressors talk to each other - Complexity and mechanisms of cell signalling - The main components of cell signalling - Types of ligands and receptors - Major post-translational modifications and the contribution of Dundee scientists - How RTKs play a role in cancer - Targeting kinases in cancer: Malignant melanoma - Ubiquitin proteasome system
Types of signal molecules (8)
- growth factors
- hormones
- interleukins
- interferons
- chemokines
- extracellular matrix proteins
- toxins
- neurotransmitters
What is angiogenesis
the formation of new blood cells
Different modes of signal transmission (4)
- conformational-coupling (performed complex)
- conformational-coupling (diffusion-dependent complex formation)
- posttranslational modification
- protein degradation
Discovery of Src
- Rous discovered Sarcoma in chickens was transmissible and a virus
- V-Src can transfer Src to avian species and cause cancer (chickens only)
- V-Src is identical to protooncogene C-Src (no infection needed)
Targeting RTKs for therapy
- EGFR is one of the most highly mutated oncogenes
- targeting RTKs involves inhibiting or blocking their activity using drugs or degradation / downregulation
EGFR mutation
- one of the most highly mutated oncogenes (pro-growth)
- gene encodes for RTK
- constantly sends cells through the cell cycle
How can EGFR gene be mutated
- amplification (overexpression of receptors)
- point-mutation (regulated by ligand binding)
- deletion (unregulated)
HER2+ cancers
- e.g. breast cancers
- mutation (prob amplification) drives cell through cell cycle
- cells dimerise, forming heterodimers, leading to phosphorylation of tyrosine on cytoplasmic tails of EGFR, and go through cell cycle
HER2- cancers
- gene is not mutated or diving proliferation of cells
How can cancer develop with no mutation in EGFR gene
- changes in ligands of receptors
- overexpression
Targets for cancer treatments
- TKI (tyrosine kinase inhibitors)
- monoclonal antibodies
Action of TKIs
- bind ATP binding pocket, mimicking ATP
- either competitive or non competitive
- kinase cannot phosphorylate substrate and signal will not be sent for cell to go through cell cycle
- cell arrest
The action of monoclonal antibodies
- antibodies isolated in lab
- bind the extracellular domain (ectodomain) of some/all of EGFR family members
- block ligand binding
- block dimerisation
- recruit immune cells
- deliver toxins to tumour
Why is it essential to treat all 7 types of EGFR family member mutations
- ## EGFR acts differently depending on which region of the body it is in
Malignant melanoma
- can be benign or malignant
- more than 70,000 cases a year in USA with 8800 deaths
- White people are 10x more vulnerable than African Americans
- one of the most common cancers in people under 30
Normal gene function of BRAF
- provide instructions for making protein that helps transmit chemical signals from outside the cell to cell nucleus
- part of RAS/MAPK pathway (regulates proliferation, differentiation, migration, and apoptosis)
Mutation of BRAF
- all mutations found within kinase domain
- single substitution (V599E) accounts for 80% of mutations
- mutated BRAF proteins have elevated kinase activity
- RAS function is not required for the growth of cells with V599E mutation
- BRAF commonly activated by somatic point mutation in human cancer
- RAS function is not required for the growth of cancer
BRAF V600E tumours
- increased proliferation of CCND1
- strong feedback from DUSP and SPRY
Targeting mutant BRAF
- inhibitors targeting “active protein kinases
- structure-guided discovery approach
- PLX4720 -> preferentially inhibits BRAF(V600E) kinase
- induces cell cycle arrest and apoptosis exclusively in BRAF(V600E)+ cells
Clinical efficacy of vemurafenib
- strong initial effects
- emerging drug resistancy
- recurrence of aggressive tumours (why?)
Paradoxical activation of ERK signalling
- underpins resistance to vemurafenib
- each patient has different signalling
- when given a single drug, it will come back
Why are anti-cancer monotherapies so ineffective
- if one cell is resistance there is 0 chance of it working due to cell proliferation
- change of one cell being resistant to multiple drugs is very low
What post-translational modifications are involved in signal transduction
- phosphorylation
- ubiquitylation -> essential for protein degredation