L04: Cell Signalling And Cancer Flashcards
What is intracellular signalling
A set of events that occur inside a cell to a specific stimulus with a specific cellular response
What events does cell signalling allow
Survival
Proliferation
Differentiation
Apoptosis
What are the signalling molecules that can trigger a intracellular response
Hormone
Cytokines
Growth factors
Neurotranmistters
What type of molecule binds to intracellular receptors
Hydrophobic
What type of molecules binds to cell surface receptors
Hydrophilic
Name an important cell surface receptor family
Receptor tyrosine kinases
Where are receptor tyrosine kinases bound to
Single plasma membrane
How many domains does receptor tyrosine kinase have
Intracellular domain
Extracellular domain
Where is the intracellular domain found
Within the cytoplasm behind the plasma membrane
Where is the extracellular domain found
Outside the plasma membrane
For all receptor tyrosine kinases which domain is the same
Intracellular domain
What is the intracellular domain of the receptor tyrosine kinase made of
Tyrosine kinase domains
What is the role of tyrosine kinase domain
Phosphorylate target proteins
Which domain of the receptor tyrosine kinase vary
Extracellular domain
If the extracellular domain of receptor tyrosine kinase vary what does this mean
Different proteins can bind to it
What are the 2 types of tyrosine kinase receptor transduction signalling pathway when signalling molecules interact with TPR
1) mitogen activated protein (MAP) pathway
2) phosoptidylinositol (pi)-3 kinase pathway
What is the main output of the MAP kinase pathway
Cell growth (cell getting bigger) Cell profileration (cell dividing in numbers)
What happens to the TPR when a signalling molecule binds to it
Dimerisation of receptor
What happens when receptor dimerisation occurs
Kinase domains of neighbouring receptors cross phosphorylate eachother on multiple tyrosine residues
What is the phosphorylation of neighbouring receptors on tyrosine residues known as
Auto phosphorylation
What does autophosrylation creature
High affinity for:
MAP pathway
PI-3 kinase pathway
Which molecule for the MAP pathway recognises the phosphorylated tyrosine residues in TPR
Grb-2
What are the 2 domain of Grb-2
SH2 domain
SH3 domain
Which domain of grb-2 binds to the phosphorylated tyrosine resides
SH2 domain
What does the SH3 domain of the Grb-2 bind to
Protein called sos
What does the grb-2 and sos complex enable
SOS to recruite and acitvate RAS
What is RAS
A G protein with GTPase activity
What is ras known as in cancer
Oncogene
Where is ras attached to
The plasma membrane next to the TPR
How does sos active RAS
SOS exchanges GDP (found in inactive ras) to GTP to activate ras
What does active ras do
Activates RAF by inducing a conformation change to it
When RAF is activated what does it do
Activates Mek by phosphorylating it
What does active mek do
Active Erk by phosphorylation
What does ERK do
Moves into the nucleus and phosphorylates proteins that include gene regulatory proteins that cause change in gene expression
What are the genes active by Erk
C-jun C-fas C-MYC C-MYC Cyclin D
What does ERK overall do
Cell proliferation and cell growth
In normal conditions how is MAP kinase regulated
Switching acitvated TPR
Inactivating ras
Inactivate target proteins
How is activated TPR switched off
By a protein protein tyrosine phosphotases
How is active ras inactivated
Via ras GAPS
How are target proteins inactivated
De phosphorylation by serine/threonine phosphatase
What can happen for cancer to develop due to MAP pathway
Proteins can become permanent turned on
What are the main outputs of PI-3kinase pathway
Cell survival
Cell growth/proliferation
Which molecule of the PI-3 kinase pathway recognises the phosphorylated tyrosine residues on RTK
PI-3 kinase
When PI-3 kinase binds to tyrosine residues what does it do
Become activated
What does acitvated PI-3 kinase do
Phosphorylate PI(4,5)P2 TO (PI,3,4,5)P3
Where is PI(4,5)P2 found
Attached to plasma membrane next to the RTK
What happens when we have PI(3,4,5) P3
PDK1 and AKT proteins bind to it
Which molecule binds to PI(3,4,5)P3 first
PDK1
When PDK1 binds what happens to AKT that is also bound to another PI(3,4,5)P2
PI(3,4,5)P3 that had PDK1 bound to acitvates AKT by phosphorylating it
What other molecule is AKT phosphorylated by
MTOR
As a result of phosphorylating AKT what happens to it
It becomes active
What does active AKT DO
Phosphorylate Bad
What is the bad
A protein that bind to inactive apoptosis inhibitory protein
What happens when active AKT phosphorylates BAD
Acitve apotosis inhibitory protein becomes released from bad and this prevents apoptosis i.e promote cell survival
How is PI-3 kinase pathway regulated
Switch TKP
De phosphorylate target proteins
Remove phosphate from PI(3,4,5)P3
How it active TKP swithched off
Protein tyrosine phosphatase
How is target proteins de phosphorylated
Serine/threonine phosphatase
What removes the phosphate from PI(3,4,5)P3
PTEN
If the MAP and PI-3 kinase pathway is disrupted what can this lead to
Cell proliferation and cancer
How can we treat people with cancer that have disrupted pathways of MAP or PI-kinase pathway
Personalised medicine
What is HER2
Member of EGFR family (type of receptor tyrosine kinase)
How does HERF2 usually work
Heterodimerise with another EGFR receptor in repsonse to the signalling molecule of EGF to activate the PI3 Kinase and MAP pathway
What does dimerisation of EGFR lead to
Activation of MAP and PI-3 kinase pathway for cell survival and cell growth
In cancer what can happen to HER2
Become over expressed
Which type of cancer shows overexpression of HER2
Breast cancer
In cancer with overexpression of HER2 what happens
Homodimerisation of HER2 (i.e phosphorylation of 2 HER2) which triggers cell growth and survival in the absence of EGF
What personalised medicine can be used to prevent HER2 overexpression
Herceptin
What does herceptin cause
HER2 degradation
Antibody dependent cellular cytotoxicity (APCC) response
What patients can herceptin be used on
HER2 positive patients (not in HER2 normal patients)
What is BRC-ABL
Oncogenic protein
How is BCR-ABL formed
Translocation of chromosome 22 and 9
Which cancer is BCR-ABL seen in
CML: chronic myelogenous
In a normal cell what is ABL
A tyrosine kinase protein that promotes cell survival and growth by dimerising tyrosine residues on RTK and activate MAP and PI3 kinase
What happens when BCR joins to ABL to form BCR-ABL
It promotes acitvation of ABL which goes onto dimerise tyrosine residues on RTK
What type of personalised medicine can be used to target BCR-ABL
Imatinib
What is the role of imatinib
Binds to kinase domain of ABL to prevent ATP binding cannot phosphorylate itself to cause downstream signalling
