Cell-cell communication lectures

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  • Created by: Sarah
  • Created on: 03-05-17 13:03
what is an example of an amino acid that is a signalling molecule?
glutamate and glycine
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examples of gases that are signalling molecules?
CO, NO
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what are the 3 types of communication?
1) passive 2) direct cell-cell commu 3) contact mediated by receptors
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what is an example of passive signalling?
NO
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what does NO do?
released from endothelial cells, in bv relax SM, increase diameter of lumen, bidns directly to enyzme to relax muscle
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where are gap junctions found?
cardiac muscle and liver
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how much of the liver membrane is made up of gap junctions?
3%
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what do gap junctions do in cardiac muscle?
synchronise muscle contraction
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what is paracrine signalling?
signalling to neighbouring cells, doesn't travel far or is destroyed
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what do bifurcation proteins do?
take the message to other pathways
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what is autocrine signalling?
cell makes ligand that binds to itself
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what kind of signalling does cancer use to stimulate its own growth?
autocrine
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why do signalling cascades have different outcomes?
1)different sig molecules and recs 2) complement of intracellular sig molecules in cell
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what do multiple steps allow?
modulation and amplification
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what do adaptor proteins do?
bring signalling proteins closer together, do not participate
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what latent gene regulatory proteins do when activated?
move to nucleus
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what are the basic steps in receptor mediated signalling?
1) synthesis of sig molecule 2) release (exocytosis or passive), transport by blood or ECF 3)detection by rec on or in cell 4)intracellular signalling cascade 5) target pro signal gets to 6) outcome
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what are the 2 broad classes of receptor types?
cell surface or intracellular
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what are some cell surface receptors?
1)contact dep (ligand) recs 2) rec with ion channel 3) G protein linked 4) enzyme linked rec
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all of the routes of signalling?
autocrine, paracrine, endocrine, synaptic, contact dependent
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what is contact dependent signalling?
juxtacrine sig, ligand +rec are membrane proteins
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what is autocrine signalling used for?
cancer cells for proliferation, reiforce developmental decision
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if paracrine molecule goes to far what happens?
its destroyed by an enzyme in the ECM
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what is endocrine signalling?
long distance signalling, transported by blood eg hormones
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what is synaptic signalling used for?
neurons to communicate with other neurons or cells
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what do transducer proteins do?
convert signal into another form
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what do relay proteins do?
pass on the message
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what do integrator proteins do?
integrateing signals from diff pathways before passing on the message
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what can intracellular signalling pathways do?
amplify signal strength (positive feedback), integrate pathways, negative feedback to terminate signal
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how do intracellular signalling cascades amplify signal strength?
one ligand is amplified into many intracellular effectors
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how do intracellular signalling cascades integrate signalling pathways?
one pathway can weaken or amplify another
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what are receptors calassified by?
their structure
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what are the 4 types of receptor superfamilies?
Type:1) ligand gated ion channels (ionotropic) 2) metabotropic- G-pro coupled receptors 3)kinase linked receptors 4) nuclear receptors
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what do nuclear receptors do?
regulate gene transcription
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what recs are used for cell-cellcommunication?
enzyme linked, g-pro linked, ion channel linked, intracellular receptors
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what do ligands need to be in order to get to intracellular receptors?
small hydrophobic molecules
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examples of small hydrophobic ligands for intracellular receptors?
steroid hormone, thyroid hormones and vitamin D
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what receptors are usually for ligand gated-gene regulatory pros (ligand binds-affects gene reg)
intracellular receptors
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what is a type of intracellar receptor?
nuclear receptors
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what domains do nuclear receptors have?
dna binding domain (to affect transcription), transcription activating domain and ligand binding domain + inhibitory protein
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sequence of events with nuclear receptors?
ligand binds to ligand binding domain causes the inhibitory protein to diassociate
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what can ion channels be gted by?
1)intracellular/extracellular ligands 2) change in m voltage 3) mechanical stretch (mechanoceptors)
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what is the most abundant type of cell surface receptors?
g protein linked recs
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what subunit is GDP bound to in a G protein?
alpha subunit
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are ligand gated receptors normally open or closed? why?
closed, binding of ligand open channel pore
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what are ligand-gated receptors classified by?
the ligand/NT that gates them (glutamate and ATP)
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what is it called when channels only let specific ions through?
ion selectivity
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what is the strucutre of all GPCRS?
7 TM domains, single polypeptidte chai, no pore or enzyme activity
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what are GPCRs involved in the regularion of?
immune response, pereption of pain, food intake, bp, sleep, mood, control of cancer growth
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half of the drugs in use target what type of receptor?
GPCRs
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what does the ligand binding to a GPCR do?
induces a conformational change that starts an intracellular signalling cascade
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what does the conformational change caused by the ligand binding to the GCPR cause?
the G protein to dock with receptor
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what does the conformational change do to the alpha subunit?
a) hydrolyse GTP -> GDP b)dissociate from B+Y subunit
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what do the subunits (alpha subunit and Y+B subunit) do once activated?
activate other proteins
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how is a G protein inactivated?
alpha subunit hydrolyses GTP->GDP, which causes inactivation of alpha subunit so it regains affinity for BY subunits when back together inactivates both subunits
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what are the downstream targets for the alpha subunit?
1) adenylyl cyclase 2) guanylyl cyclase 3) phospholipase C
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what is the downstream target of BY subunit?
ligand-gated ion channels
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what are the types of G proteins classified by?
three main types of alpha subunits
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what are the types of G proteins (types of alpha subunits)?
1) Gs (stimulates) 2) Gi (inhibits) 3) Gq
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what does Gq G protein do?
stimulates phosolipase CB
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what does Gi inhibis?
adenylyl cyclase and guanlyl cylase
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what does Gs stimulate?
adenylyl cyclase and gunaylyl cyclase
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what cells does cAMP (cyclic AMP) play a role in?
all studied cells
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what is the size of cAMP?
approx0.1um
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how is ATP turned into camp?
loss of two phosphates by adenylyl cyclase
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what does andenylyl cyclase do?
converts ATP to cAMP
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what is cAMP rapidly destroyed by?
cAMP phosphodiesterase
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what type of kinase is protein kinase A?
a serine/thereonine kinase
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what is protein kinase A dependent of?
cAMP
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what is inactive PKA made up of?
2 regulatory subunits, 2 catalytic subunits
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how do you get the active catalytic subunits of PKA?
cAMP binds to the regulatory subunits which actives the catalytic subunits
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PKA active catalytic subunits catalyse what reaction?
phosphorylates glycogen phosphorylase
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once glycogen phosphorylase is phosphorylated what can happen?
glycogen --> glucose 1-phosphate by glycogen phosphorylase
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what fastf action does PKA mediate?
changes in seconds from glycogen to glucose 1 phosphate
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what is the slow PKA mediated activation?
gene transcription, takes hours
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what is the reaction with PKA in gene transcription?
PKA phosphorylaytes CREB so CREB binding pro binds to it
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what do kinases do?
add phosphate groups
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what do phosphatases do?
remove phosphate groups
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what does PKA do?
is a kinase so adds phosphate groups
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what do protein phosphates do to PKA signalling?
terminate signalling by PKA
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what happens to PIP2?
ligand binds -> activates G pro->activate alpha bit -> activates phospholipase c enzyme -> converts PIP2 to DAG + IP3
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what does phospholipase c do?
cleaves phosphate group off of PIP2 from lipid tails -> get DAG (tails) and IP3 (heads)
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what G proteins activate phospholipase Cb?
Gq alpha subunit
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phospholipase cb hydrolyses what?
PIP3 = phosphatidylinitol45 bisphosphate
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what is phosphatidylinisitol 4,5 -bisphosphate hydrolysed into?
DAG (diacylglycerol) + IP3 (inositol 1,4,5, triphosphate
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what happens to DAG?
is membrane bound
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what happens to IP3?
diffuses in cytosol
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Where does IP3 diffuse and binbd to?
diffues to ER binds to calcium channel
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What does IP3 do at the ER?
releases calcium store from ER into cytosol
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what is calcium going to go off and do?
further signalling events
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how is IP3 terminated?
mediated increase in calcium ions, dephosphorylated or phosphorylayted
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what is IP3 dephosphorylated to?
IP2
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What is IP3 phosphorylated to?
IP4
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what does DAG (in M) activate?
protein kinase C
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what causes protein kinase C to move to the plasma M (where DAG is)
Calcium ions
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what happens to PKC in the membrane?
it is activated by DAG and bound calcium
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what does activated PKC do?
phosphorylates target proteins
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what do the calcium ions in the cytosol cos of ip3 do?
bind to PKC, PKC moves to M, activated by DAG, PKC goes off and phosphorylates proteins
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what is the structure of enzyme linked recs?
single pass recs made from a single polypeptide chain
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what are some examples of enzyme linked receptors?
growth factors NDF PDGF, GDNF
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what happens once a ligand binds to an enzyme linked receptor?
ligand binds -> dimerization (pulls 2 bits of rec together) of receptor ->activation of intrinsic enzymatic activity
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where does kinase enzymes transfer the phosphate group to?
amino acids of proteins
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where does the phosphate group that kinase adds to something come from?
ATP
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what amino acid does tyrosine kinases add a phosphate to?
tyrosine residues
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what kinase adds a phosphate to serine.threonine?
serine/threonine kinases
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what are the classes of ezyme linked recs?
1) rec tyrosine kinase 2) rec serine/threonine kinase 3) tyrosine kinase-linked rec 4) histidine-kinase associated rec 5) receptor guanylyl cyclase
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which enzyme linked recs have the receptor being an enzyme?
rec tyrosine kinase, rec serne/threonine kinase, rec guanylyl cyclase
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what enxyme linked rec have the enzyme associated?
tyrosine kinase limked rec and histidine kinase associated rec
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what is the most abundant class of enzyme linked receptor?
receptor tyrosine kinases
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what happens with rec tyrosine kinase?
signal molecule binds -> dimerisation -> activates intrinsic tyrosine kinase activity in intracellular part -> autophosphorylation/crossphosphorylation
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what do autophosphorylated tyrosines have the advantage of?
multiple outcomes, range of docking/activation sites
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what happens when the tyrosine kinase gets a phosphate group taken off?
relay proteins come and take the phosphate activates other proteins
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why is tyrosine kinase involved in cancer?
muatted rece tyrosine kinase acts without a ligand binding
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what is the tyrosine kinase split up into?
tyrosine kinase domains
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what does src bind to?
phosphorylated rec tyrosine kinases
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what domains recognise the phosphorylated tyrosine kinase?
SH2 binding domain
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what is the src binding region called?
src homology domain (SH")
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what is src?
a tyrosine kinase and phosphorylates other signalling proteins in a phosphorylation cascade
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what are the downstream targets of receptor tyrosine kinases?
1)Ras/MAP kinases 2) PI3 kinases 3) phospholipase C
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why is ras a type of G protein?
its a proein that binds and hydrolyes ATP
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how is RAS protein activated?
exchanging GDP for GTP
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How is Ras protein deactivated?
hydrolysis of GTP
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What side of the plasma memrbane is ras tethered to?
the cytoplasmic side
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what is ras protein?
a monomeric GTPase
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what does GEFs stand for?
guanine nucleotide exchange factors
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what do GEFS a(guanine nucleotide exchange factors) do?
promote exchange GDP for GTP to activate ras
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what do GTPase- activating proteins (GAPs) do?
increase the speed of hydrolysis of GTP by Ras to inactivate it
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what is trying to inactivate Ras?
GTPase activating proteins
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what is trying to activate Ras?
Guanine nucleotide exchange factors
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how do rec tyrosine kinases activate Ras?
they activate GEF proteins or inhibit GAPs
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what oncogene is most common in cancer
ras oncogene
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how is the MAP-kinase pathway activated?
by ras signalling
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what does Ras activate
the first kinase in MAPK pathway= MAP-KKK
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what is the sequence of events in the MAPK pathway?
Ras activates MAP-KKK, MAP-KKK activates MAP-KK, MAP-KK activates MAPK
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in each step of the MAPK pathway what is being used up?
ATP -> ADP
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how many serine/threonine kinases does the MAPK pathway consist of?
3
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how many MAP-KKKs and MAP-KKs can the cell contain up to?
up to 7
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how many MAP-K can the cell hold?
12
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what prevents cross-talk between parallel pathways+hold each pathway in line?
scaffolding proeins
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what activates scaffold bound kinases?
Ras
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how can the MAPK pathway be terminated?
1) rec + ligand degradation 2) GTP hydrolysis in G pro (Ras-inactived by GAPS) 3) dephosphorylation
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how does dephosphorylation to terminate the MAPK pathway work?
ErK with phosphate -> Erk (MAPK) by phosphatase
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rec tyrosine kinases activate what?
PI3-kinase
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how is PI3 kinase activated ?
by rec tyrosine kinase, lipid phosphorylation
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PI 3 kinase phospharylates membrane phospholipid at what?
carbon 3
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what G protein is activated in by RTK by activation of PI-3 kinase?
PIP2
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receptor tyrosine kinase uses what dfor PI3 kinase signalling?
PI3,4 bisphosphate and PI, 3,4,5 ttriphosphate
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how do PI(3,4)P2 AND PI(3,4,5)p3 bind and activate cytosolic signaling enzymes?
using PH domains- pleckstrin homolgy domain
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what activates Phospholipase C- y in the PI3 kinase pathway?
tyrosine phosphorylation and ativation of PLC-Y by BTK bind to them phosholipids
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how is signalling of PI3-kinase terminated? by what?
by PTEN phosphotase coverts PI(3,4)P3 TO PI(4,5) P2
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