Lecture 2- Cell signaling Flashcards
What are examples of cell surface receptors
Growth factors, EGF, Insulin
* Bind outside of cell then brings change inside the cell
Are cell surface receptors hydrophobic or phillic
- hydrophillic
- cannot pass through cell membrane
Cell surface receptors are ___ ____ proteins
Integral membrane
When cell surface receptor have a hormone bound, what happens? and what can it lead to?
- activates secondary messengers within the cell
- leads to signal transduction
Cell surface receptors can be internalized by _____ to…..
endocytosis to negatively regulate the hormone action
- Growth factors, EGF, insulin binds to the cell surfact receptor
- Signal transuction cascade/pathway occurs to cause phosphorylation cascades or conformational change
- Second messengers turn on transcription of a gene
Cell surface receptors have how many domains and what are they?
3 domins
* Extracellular
* transmembrane: through membrane
* intracellua: enzyme activity
What are the major classes of transmembrane receptors
- liganded gated ion channels
- enzyme-linked receptors
- cytokine receptors
- GPCR
example ligand gated ion channels and where we find them
Explain enzyme linked receptors
signal transduction cascade
* Hormone or Growth factor binds to the extracellular domain of its specific receptor
* Enzyme linked receptorsL receptor binding leads to activation of tyrosine kinase or serine/threonine kinase activity in the cytoplasmic domain of the receptor
Two things can happen with enzyme linked receptors
a)leads to sequential phosphorylation of intracellular signaling molecules and transduction of the signal to a biological response
b) activation of GTP binding RAS protein
explain the activation via growth factor binding–> protein phosphorylation
explain insulin signaling
explain transducer: Ras GTPase and canonical growth factor receptor
Explain the Ras activated pathway MAP kinase cascade
What are the two enzyme linked signal transduction
protein phosphorylation
* example was insulin signaling pathway
* ATP and kinase activity
Ras is an on-odd switch regulated by GTP
* GTP
* NO KINASE
Explain cytokine receptors
- Some receptors do not have intricsic kinase activity
- These cytokine receptors are associated with a protein kinase family, JAKS which when autophosphorylated recruit STATs (singal transducers and activators of transcription)
Explain the JAK STAT pathway
- Cytokine binds
- turn on JAK activity and is auto phosphorylated
- once JAk is phos, then recruit stat which gets phos (activated)
- Activated STATs dimerize and translocate to nucleus
- Bind to promotor region to recruit co-activators to transcribe genes for growth, proliferation, cell fate determination, stem cell renewal
What binds to the receptors in the JAK STAT pathway
cytokines
What are G protein coupled receptors (GPCRs)
7 transmembrane receptor that is couple with a g protein which has its own subunits (a, b, gamma)
what are the ligands that activate GPCR
Ca++
Odorants
pheremones
small molecules
* aa, amines
* n.t., n.s.
* prostaglandins, PAF
* peptides
Proteins
* TSH
* LH
* FSH
* interleukins
* chemokines
What is the response when the ligand is bound
Activates g-protein which in returns actives effector membrane enzymes or channels–> activate 2nd messengars
Review: insulin goes through what?
Sequential phosphorylation
What binds in JAK and STAT
cytokines
When is RAS activated
GTP bounded
GPCR takes multiple number of ligands which then…
activates G protins that has 3 domains which then activates the membrane effector to create 2nd messengers
When is G protein activated and inactivated
activated:GTP
inactivated: GDP
What happens when GTP binds to teh G protein
GTP binds to the alpha subunit and beta+gamma dissociate away from alpha
Which G protein subunit(s) is associated with enzyme activity?
alpha
What subunit(s) works with the opening and closing of ion channels
beta and gamma
alpha subunit can activate what two enzymes
- adenylyl cyclase
- phospholipase C
When the adenylyl cyclase is activated what is the response
ATP activate cAMP (2nd messanger) which then activates the activates protein kinase A to phosphorylation of other targets
What happens when phospholipase C is activated?
Cleaves phospholipids to get DAG (2nd messenger ass. with membrane).
* DAG can then activate protein kinase C to get protein phosphorylation
OR
- DAG activates IP3 (inositol triphosphate, 2nd mess) to regulate Ca+2 channels
what do pharmaceuticals majorial target
GPCRs
How does GPCR regulate so many differenct activites?
alpha subunit
What is the subclasses of the alpha subunits and their functions
ai: ion channels, inhibition cAMP
as: increase (stimulate) cAMPA
aq: phospholipase C
ai2: Pho GEFs
What does ai do
ion channels
inhibition cAMP
What does as do
increase cAMP
how do we pick ai or as
by the type of ligand that binds
hormone or n.t activates adenylyl cyclase to do what?
activate as which in return stimulates g protein
hormone or n.t inhibits adenylyl cyclase to does what?
activates ai in return to inhibit g protein
what are the commone second messengers
- Ca+2
- 3,5 cyclic AMP and GMP
- 1,2-Diacylglycerol (DAG)
- Inositol 1,4,5-triphosphate (IP3)
Example how camp regulated protein kinase A
Patel talked about how back in the day (1993) about decreased and increase signal transduction
decreased signal transduction
* decrease gene expression or impaired expression
Increased signal transduction
* increase gene expression or impaired expression
Decrease or increase is not a good thing–> disease
cancer is impaired signal transduction
How do we target signaling pathways for drugs
Block the receptor
* Shut down growth factor
* ex. herceptein
* blocks receptors so growth decreases
Target cancel cell with antibody-tozin conjugate
* if you want to target a particular cell type and not affect other ones you use radioisotype
* radioisotype is bound to antibody which is bound to antigen which targets receptor
drugs targets G protein coupled receptors (GPCRs)
- inhibit signaling pathways
- target cell bc of these receptors
- act as competive inhibitors
signal transduction pathway cross-talk
- have gene expression change
- different amount of protein that is present
explain signaling cascade
a hormone binding to its receptor activates the signaling cascade–> amplification of signal
* hormones can bind to multiple receptros before being degraded
* each receptor can activate several enzymes
* these enzymes produce seconf messengers
* results in transcription of several genes, and other metabolic effects–> ex. uptake of glucose
What are the modes of down regulation of signaling
- upcoupling of the receptor from signaling cascade: receptor inactivation
- Receptor internalization: endosome
- receptor down-regulation: lysosome
