20 – Cells & their Environment III: Long-term signals Flashcards
Long term signals = changes in
gene expression
> 100 early-response genes trigger S-phase (when DNA is replicated)
Growth factors
stimulate cell proliferation & survival
discovering Growth factors experiment with chick embryo
Chick embryo - added extracts - trigger proliferation
-Extract treated with snake poison (containt nucleases degrade DNA to nucleotide & high concentration of growth factpr)
…receive signals from growth factors
Receptor tyrosine kinases
Tyrosine kinase
phosphorylate tyrosine residues
what happens to receptor tyrosine kinase
- Ligand binds to receptor
-Growth factor = ligand
-Receptor = receptor tyrosine kinase
-Receptor in exterior
-Kinase in cytosol - Dimerization reaction happens when ligand bound to receptor
found in almost all human cancers
Aberrant/abnormal RTK signaling
how cells can know about what’s happening in their environment based on RTK.
coming together of monomeric proteins to form a dimer triggers phosphorylation and trans creates that signal.
3 ways that we have for cells to have information come across the plasma membrane,
a separation, a conformational change, and a dimerization in each of 3 different contexts.
steps to what happens when dimerization happens
dimerization will bring intracellular kinase domains into close proximity with one another.
the kinase itself is poorly active, and it has a domain: activation loop = little arm structure that’s shown pointing downward.
The first thing that happens upon ligand binding and successful
dimerization = 2 kinases phosphorylate each other’s activation loops = arm swung up/pointing out & phosphate group attached to it
once those activation loops are active=what triggers abundant auto phosphorylation in trans.
both are accumulating amount of phosphate groups.
start signaling cascade
signaling cascade: 1st thing that happens
Phosphorylated RTK = recruit additional signaling proteins
Ras
small GTPase & most common mutation in human cancer
-Rat Sarcoma
-Constitutively-active Ras
20-25% of all cancer
>90% of pancreatic cancer
rat cells to express a version of the rat’s own proteins, A gene that was itself found in the rodent genome= small GTPase Ras.
1st domains that get recruited to the active receptor tyrosine kinases & what does it do?
SH2 domains
-recognize & bind to phosphorylated tyrosine residues (sticks into a groove on SH2)
They get recruited up onto the dimerized RTK protein
Sh2 domian contain an important protein… in case of RTK, and what does it do?
GRB2
1st bind to phosphorylated tyrosine.
then recruit a Sos protein
Sos will bind to Ras and act as a GEF for the Ras.
SH3 domains
bind proline-rich peptides: Pro4 & Pro7
o Creates kink in polypeptide chain
the Ras pathway
proline peptides bind to the SH 3 domain and GRB2 use its SH2 domains to recognize the RTK.
It uses its SH3 domains to recruit Sos
Sos will bind to Ras and trigger its activity, leading to downstream signaling
Active Ras triggers
kinase cascade
order of proteins:
RTK- GRB2-Sos-Ras-Raf-MEK-MAPK
kinase cascade
- active Ras recruit and bind to the regulatory domain of a RAF kinase
-inactive RAF has a regulatory domain
= release activity & RAF is active. - RAF phosphorylate activation loop of MEK
- MEK activate MAPK
-activation loop being phosphorylated. - MAP K is active = translocate into nucleus where it activates TF
Activated kinases at end of chain will…, leading to…
phosphorylate TF
leading to proliferation
MAP kinase cascade control
Budding yeast mating decision
budding yeast:
2 sexes of yeast: a & alpha
-shmooing
shmoo of both sexes fuses = temporary diploid = sporulate into haploid organims
Mating decision
switch-like
-Phosphorylation = on switch to shmoo
-Concentration response = curve
why is concentration for schmooing switch like?
a type yeast, they need to know that they are in close enough physical proximity to an alpha type yeast that mating is possible.
And it is only when that concentration crosses critical threshold that the A type yeast knows that it is in physical proximity to alpha type yeast.
switched into proliferative state, the wall of pushing back with phosphatase is broken, so everything is being turned on, therefore, switch like
Metastasis requires
cells to break connections with their neighbors
