Cell Communication Flashcards
define signal transduction
cell to cell communication
in general how does signal transduction work?
- extracell signal binds to receptor protein on memb.
- binding causes an intracell signal to be released
- intracell signal activates effector proteins
- effector proteins cause the outcome
what are 3 outcomes of effector proteins?
- altered metabolism
- altered gene expression
- altered cell shape or mvt
more specific signal transduction definition
extracellular signaling molecules bind to specific receptors in target cells to initiate a chain of events
external signals induce 2 major types of responses
- fast response
2. slow response
fast response
change in activity or function of enzymes or proteins in cell
slow response
change in amounts of proteins by change in gene expression
signal transduction process
- ligand
- high affinity receptors
- intracell signal proteins
- effector proteins
- outcome
list the types of signaling
- endocrine
- paracrine
- synaptic
- autocrine
- direct cell
long distance signaling
endocrine signaling
endocrine signaling
long distance, long half-life
signal enters blood stream and travels to reach it’s target
local signaling
paracrine signaling
or
synaptic signaling
paracrine signaling
local, not freely diffusible
affects the nearby cells
synaptic signaling
acts locally
affects nearby axons/dendrites using neurotransmitters
signals to the cells that released the signal
autocrine signaling
autocrine signaling
cell releases a signal to affect itself and/or cells of same type nearby
ex. growth factors
immune cell signaling
direct cell signaling
ex. Ag presenting to T cells
each cell interprets all the signals it gets to determine what to do…..
survive
die
divide
differentiate
signals
or ligands
typically secreted via exocytosis
signal types decides where signal goes
receptors
bind specifically to signal molecules w/ high affinity
because signals are produced in low levels
effectors
the targets of receptors intracell
alter cell activity to create 2nd messengers
main types of ligands
- small lipophilic - hormones
2. water soluble molecules or hydrophilic
general types of receptors
- cell surface receptors
2. intracellular receptors
describe intracellular receptors
steroid receptors - can be present in cytosol since the signal can easily pass thru the bilayer
7 transmembrane receptors
or G-protein coupled receptors
describe the structure of G-protein coupled receptors
have 3 domains
- extracell - binds ligands
- transmemb. - anchors
- cytoplasmic domain - associates w/ G protein
G-proteins
heterotrimeric proteins composed of 3 subunits (a b g)
GTP or GDP
describe the steps of G-protein relaying signals
- ligand binds receptor
- conformational change occurs in receptor
- receptor binds to G
- receptor acts as GEF
- GDP exchanged for GTP
- Ga is now active an binds to effector to activate it
adenylyl cyclase
an effector protein that catalyzes formation of cAMP
which is the 2nd messenger that can cause a biological response
reset of G-protein system
hydrolysis of GTP bound to Ga occurs
Ga inactivated and recycled/sent back to starting point
what is the significance of a G-protein coupled receptor acting as a GEF?
guanine exchange factor
it exchanges the GDP for a GTP which causes Ga to become activated
it exchanges, not phosphorylating
Gas
stimulating Ga type
stims adenylyl cyclase
Gai
inhibiting Ga type
inhibits adenylyl cyclase
cAMP
a 2nd messenger
activates a protein kinase called PKA
PKA
a protein kinase activated by cAMP
can phosphorylate proteins to either activate or inactivate them
PKA structure
inactive form - has 4 subunits
2 catalytic, 2 regulatory
active form - the 2 catalytic units released as separate entities
binding of cAMP to PKA
2 cAMP binds to each regulatory subunit (so 4 total)
causes the 2 catalytic units to be released from the regulatory units
how does phosphorylation change a proteins function?
it changes the shape of the protein
and protein shape determines it’s function
what is meant by amplification of signaling?
a single ligand receptor event can activate multiple effector protein to generate hundreds of 2nd messengers which effect 1000’s of proteins
what is desensitization of a signal?
ability to turn off or reject the signal
important for preventing cancer cell growth
list the 5 ways to stop a signal in a signal transduction pathway
- receptor sequestration
- receptor destruction
- hormone level drop
- signal removal
- GRKs
receptor sequestration
invagination of the membrane to take the receptor off the cell surface
thus the cell cannot receive signals
receptor destruction
cell invaginates the signal
the endosome combines w/ lysosomes
receptor protein destroyed
thus the cell cannot receive signals
dropage of hormone levels
decreases adenylyl cyclase activity
which decreases cAMP
which decreases PKA
thus decreases/stopping the signal transduction pathway
removal of signaling molecules
phosphodiesterase will remove cAMP
thus no 2nd messenger - no outcome
define GRKs
G-protein receptor kinases
capable of phosphorylating G-protein coupled receptors
GRK effects
- phosphorylates a receptor
- now the protein arrestin will bind
- results: receptor cannot act as GEF
thus signal pathway stopped since Ga cannot be activated
arrestin
- -a protein that can bind to a G receptor after GRK binds
- -binds to the 3rd intracell loop
- -which prevents Ga from interacting w/ loop 3
resulting in Ga not being converted to Ga-GTP
PKA: addition of 2 negative charges can change ….. ?
the conformation of the protein thus changing it’s function
GPCR
G-protein coupled receptor
other G-protein variants
Gao
Gaq
variant G-protein GPCR pathway: signal to 2nd messengers
- ligand binds
- GPCR binds Gao/q
- GPCR acts as GEF
- active Ga binds to phospholipase C
- phospholipase C cleaves PIP2
- produces IP3 and DAG
IP3
produced when phospholipase C cleaves PIP2
binds to IP3 ligand gated channels on ER to trigger opening to release Ca into cytosol
DAG
produced when phospholipase C cleaves PIP2
works w/ Ca to activate PKC
PKC
protein kinase C
Ca and DAG both bind to and activate PKC
PKC undergoes conformational change and can now phosphorylate a variety of substrates
2 roles of Ca discussed in cell signaling
- working w/ DAG to activate PKC
2. binding to calmodulin to activate it
calmodulin
Ca binds to activate it
can bind to different cellular proteins to activate their functions
calmodulin example
binds to CaM kinase II
which can then phosphorylate transcription factors to induce transcription
list the other 3 types of signal transduction
- tyrosine kinases
- jak-stat receptors
- serine/threonine kinases
RTK purpose
play important role in signal transduction
are used in response to growth factors
growth factor = ligand/signal
RTK domains
- extracellular domain
- transmembrane domain
- cytoplasmic/enzymatic domain
RTK extracellular domain
ligand binding
ligand for R7 = Boss
RTK ligand binding
- -causes conformational change
- –2 receptors dimerize
- —autophosphorylation occurs
autophosphorylation
occurs in ligand bound RTK receptors
causes receptors to act as scaffolding/docking sites to recruit other proteins to plasmalemma
RTK transmembrane domain
anchors the receptor in the plasmalemma
RTK cytoplasmic domain
- -has a tyrosine kinase domain that acts as enzymatic domain
- -where the signal transmits thru
what does RTK signal transmittance thru ______ result in
thru tyrosine kinase domain to phosphorylate protein attached
RTK pathway
- growth factor binds
- RTK dimerize, autophosphorylate
- RTK binds to SH2 of Grb2
- SH3 of Grb2 binds to SOS via prolines
- SOS acts as GEF to Ras
- Ras-GTP binds to Raf
- active Raf initiates Map kinase pathway
what does the Map kinase pathway lead to?
changes in gene expression
to result in cell proliferation
what are the more direct routes for impacting transcription?
- jak-stat
2. smad
what initiates the MAP kinase cascade
activate Raf via the binding of Ras
MAP kinase cascade is propagates the signal downstream by using ?
ATP to phosphorylate the next substrate
list the Map kinase cascade
- Raf activates Mek
- Mek activates Erk
- Erk enters nucleus
resulting in changes in gene transcription to cause cell proliferation
map kinase kinase kinase
raf
map kinase kinase
mek
map kinase
erk
MAP
mitogen activated protein kinase
results in cell proliferation
JAK-STAT pathway
- ligand binds receptor
- receptors dimerize
- 2 jaks bind
- jaks phosphorylate each other and receptors
- receptor binds 2 stats and phosphorylate them
- stats separate, dimerize, enter nucleus, bind to DNA
- causing transcription of target genes
janus kinases
JAK
many signaling molecules are ________ that can mutate into oncogenes and cause _____ .
protooncogenes and cause cancer
STAT
signal transducer and activators of transcription factors
example of jak-stat pathway
kidneys produce erythropoietin which employs the jak-stat to initiate signaling to result in increased production of RBCs
R-Smad =
receptor specific smad
Co-Smad =
common smad
R-smad forms a complex w/ ?
co-smad
how is the receptor activated in the smad pathway?
via phosphorylation
Serine/Threonine pathway
= smad path
- receptor activated
- receptor binds to r-smad and phosphorylates it
- active r-smad dissociates and binds to co-smad to create complex
- complex moves into nucleus
- impacts target genes for transcription
what the example of the smad pathway used in class?
hereditary hemochromatosis
iron metabolism - expression of hepcidin
hepcidin
protein made in liver that regulates the uptake of Fe
binds to Ferroportin in intestinal cells to cause invagination and proteolysis of ferroportin
high hepcidin levels
= no fe uptake
low hepcidin levels
= fe uptake via Ferroportin in intestines
iron pathway: food to blood stream
enters intestinal cells via DMT1 on apical surface
exits cell into blood via Ferroportin on basal domain
hereditary hemochromatosis
–genetic disease of uncontrollable iron absorption, leading to fe overload and organ failure
—due to mutations in hfe gene – also called C282Y mutation
significance of hfe gene
hfe binds to transferrin receptors
if mutated it cannot turn on hepcidin expression
thus no control of ferroportin
hfe works thru a ___ pathway
smad
a mutated hfe cannot signal _____ to do ?
tfR2
to start smad path to express hepcidin
point mutation in codon 12
results in Gly replaced w/ Val
this constitutively activates Ras
which is always found in human cancer
how is protein kinase C activated?
- signal binds GPCR
- GPCR acts as GEF to Gao/q
- activates phospholipase C
- it cleaves ip2
- producing ip3 and dag
- ip3 causes er to release Ca
- dag + Ca bind to PKC to activate it
describe how a mutation in hfe causes a signal transduction problem? and what does it lead to ?
if hfe is mutated it cannot bind to tfr2 to activate the smad pathway that leads to expression of hepcidin. if hepcidin is not present to regulate Ferroportin activity, this leads to iron overloading-uncontrollable absorption of iron.
leading hereditary hemochromatosis
hfe binds to ?
TfR2
