Chapter 16 Flashcards
signal transduction
converting a signal from one form to another
endocrine signal and example
long-lived ligands (hormones) that travel through the circulatory system to induce changes in distant target cells
- insulin released by B-cells of pancreas
paracrine signaling
short-lived ligands (growth factors) that affect nearby target cells (local)
secrete to ECM
wound healing, regulating inflammation at infection sites
autocrine signaling
paracrine signals where cells respond to their own signals that they secrete
- T cells (macrophages) with IL-6 secretion
- common in diseases, cancer cells/angiogenesis
neuronal signaling
release of short-lived ligands (neurotransmitters) into synapse
contact signaling
membrane bound signaling molecule binds to receptor on another cell
- important in development and differentiation
notch signaling
contact signaling where delta signal protein attaches to notch (delta receptor) on target cell
- Notch is a transcription regulator that cleaves its tail when bound to delta signal
-C-term tail enters nucleus to regulate transcription
lateral inhibition in development of fruit flies
single cell in a sheet of epithelial cells differentiates to become a nerve cell
-its delta signal protein attaches to notch on surrounding epithelial cells and inhibits them from differentiating
cell surface receptors
bind to large/hydrophilic ligands that cannot pass through PM
intracellular receptors
bind to small/hydrophobic ligands that can pass through the PM
factors that influence how different cells respond to the same signal/ligand
expression of certain receptors
intracellular relay system
intracellular targets
(same signal has different effects on different cell types)
“tailoring” of a cell response
thousands of different receptors allow cells to respond to different COMBINATIONS of those signals
fast cellular signal response
signal affects the activity of existing proteins
- skeletal muscles contract within ms because it opens existing ion gated channels
slow cellular signal response
response that requires gene triggering is slower (mins to hours)
- cell growth/ division
small hydrophobic hormones
steroids (testosterone, estradiol, cortisol) secreted by adrenal cortex, testes, ovaries
- derived from cholesterol
- bind to nuclear receptor superfamily of transcription regulators
thyroxine
thyroid hormone
secreted by thyroid gland
derived from tyrosine
stimulates metabolism in many cells
cortisol
hormone released by adrenal gland in starvation, stress, exercise
-signals the liver to increase glucose production from amino acids (upregulation of gluconeogenesis genes)
effector proteins
target of intracellular signaling molecules; change behavior of cells in various ways
functions of molecules in signaling cascade
relay, amplify, integrate, distribute, feedback
signal integration
cell can receive signal from more than one intracellular pathway and integrate them before moving signal onward
signal distribution
signals can be distributed to more than one signaling pathway or effector protein
feedback regulation of a signal
process in which late product of the pathway inhibits or activates an enzyme acting early in the pathway
two classes of molecular switches
- activated/inactivated by phosphorylation
- binding GTP (active) and GDP (inactive)
regulation of phosphorylation (enzymes)
kinases (phosphorylate): serine/threonine kinases and tyrosine kinases
phosphatase (dephosphorylate)
GEFs
Guanine Exchange Factors: activate GTP-binding proteins by promoting exchange of GDP for GTP
GAPs
GTPase-activating proteins: turn GTP;-binding proteins off by promoting GTP hydrolysis
example of ion channel coupled receptors
acetylcholine receptor in skeletal muscle cells converts chemical to electrical signal
action of enzyme coupled receptors
usually single-pass membrane proteins activate enzymes in response to signal or are enzymes themselves (mostly kinases)
examples of enzyme coupled receptors
IRE1 and PERK in UPR
GPCRs
G-protein coupled receptors; 7-pass transmembrane proteins that activate membrane-bound G-proteins (GTP-binding proteins) which initiates signal cascade
makeup of G-proteins
three subunits: alpha, beta, gamma
alpha and gamma tethered to PM by lipidation
alpha subunit binds GDP/GTP
Activation of G protein process
- Inactive G-protein is bound to GDP
- signal molecule binds to GPCR, activates receptors, GDP dissociates from G-protein
- GTP binds to alpha subunit
- alpha dissociates from beta/gamma and both can interact with proteins to further relay signal
how GPCRs turn off
alpha subunit is a GTPase that will hydrolyze GTP to GDP
Gs vs Gi (G proteins)
stimulate vs inhibit
targets of G-proteins
channels or enzymes
Channel coupled= fast/immediate
Enzyme targets (transcription regulators) take longer; most common are adenylyl cyclase and PLC (phospholipase C)
coupling of GPCRs to K+ channels
-acetylcholine binds to gcprs on heart muscle cells -> gcpr activation
-activated beta/gamma complex binds to K+ channel and holds in open conformation
- K+ released out of cell, hyperpolarization, contraction/heartbeat slows down
signals that increase heartbeat
adrenaline aka epinephrine
cholera toxin action
modifies alpha subunit of Gs; locks G protein in active state (cannot hydrolyze GTP)
-> stimulates adenylyl cyclase enzyme causing influx of Cl- and hence water into gut lumen
-> extreme diarrhea and dehydration, can be fatal
cAMP phosphodiesterase
enzyme that converts cyclic AMP (cAMP) back to AMP - terminates signal
adenylyl cyclase enzyme activity
converts ATP to cAMP
primary messengers
ligand binding
second messengers
intracellular signaling molecules released by the cell; amplify and continue signal
glucose/cAMP relationship
glucose inhibits cAMP synthesis to maintain high ATP conditions
-tells the cell more ATP doesn’t need to be made
cAMP initiates low or high energy pathways
low energy pathways
caffeine effect on cAMP
caffeine inhibits caffeine breakdown- causes fast heart rate, muscle shaking
cascade pathway of G-proteins activating adenylyl cyclase
activated GCPR activates alpha subunit of G-protein -> activates adenylyl cyclase -> produces cAMP -> cAMp binds/activates PKA -> active PKA phosphorylates downstream targets; changes protein activity
PKA
protein kinase A, activated by binding of cAMP
epinephrine (adrenaline) effect on GCPR pathway in skeletal muscle cells
stimulates glycogen breakdown
cAMP causes what output signal
varies based on what proteins get phosphorylated
cAMP induces PKA-dependant protein phosphorylation
- can regulate transcription factor activity
epinephrine (adrenaline) effect on GCPR pathway in heart cells
increase heart rate
epinephrine (adrenaline) effect on GCPR pathway in fat cells
breakdown of fats to fatty acids
adrenergic receptors
receptors that bind adrenaline/epinephrine
adrenaline GCPR full pathway
adrenaline -> GPCR activate -> G-protein activates -> adenyl cyclase activates -> cAMP production -> activates PKA ->
1. increase heart rate
2. breakdown of glycogen in skeletal muscles
3. breakdown fats to fatty acids
Response prepares body for SUDDEN ACTION
result of mutation that constitutively activates PKA in skeletal muscle cells
decrease in the amount of glycogen available since glycogen phosphorylase would always be activated
PLC
enzyme that cleaves inositol phospholipids to inositol triphosphate (IP3) and diacylglycerol (DAG)
bound to the cytosolic side of PM
result of IP3 released to cytosol
binds to Ca2+ channels at the ER, Ca spills into cytosol and has many effects as second messenger (actin/myosin contraction, neurotransmitter release)
calmodulin
Ca2+ binding protein (4 sites)
activates Ca2+/calmodulin dependent protein kinases (CaM-kinases)
CaM kinases activity
phosphorylates serines and threonines of target proteins
GCPR/NO pathway
acetylcholine binds GCPR on epithelial cells
-stimulates an increase in cytosolic Ca2+
- activates nitric oxide synthesis from Arg
- NO diffuses to neighboring cardiac muscle cells
- NO binds guanylyl cyclase which converts GTP to cGMP
-causes smooth muscle cells to relax
REDUCES BLOOD PRESSURE
examples of primary messengers
insulin, adrenalin, acetylcholine
examples of second messengers
Ca2+, cAMP, Ap3, DAG
RTKs
Receptor Tyrosine Kinases
common single-pass enzyme coupled receptors spanning PM
-binding of signal molecule causes them to dimerize (to associate together)
dimerization of RTKs
activates kinase domains (phosphorylate each other on specific tyrosine) -autophosphorylation
SH2 domain
domain on target domain that binds to phosphorylated tyrosine (docking site for SH2) on RTK
How is RTK signal turned off
-Tyr phosphatase removes phosphate
- Entire receptor can be recycles
Ras
small GTP binding protein that acts as a second messenger
-anchored to cytosolic face of PM by lipidation
-found mutated in 30% of cancers-constitutively active Ras (oncogene)
activation of Ras by RTK
activated RTK recruits Ras-GEF (via adaptor protein) to activate Ras -> onward signal transmission
Ras amplification cascade
Phosphorylation cascade of serine/threonine kinases (via ATP hydrolysis)
Ras activates MAP 3K -> activates MAP KK -> activates MAP kinase -> changes in protein activity and gene regulation
advantage of 3 kinase pathway
allows for signal integration
PI-3-Kinase-Akt Pathway
phosphoinositide 3-kinase (activated, bound to P-RTK) phosphorylates inositol phospholipid -> recruits serine/threonine protein kinase Akt (protein kinase B)
Akt activation
recruited to P-inositol phospholipid, activated by protein kinases 1 and 2 (which phosphorylate Akt)
activated by different pathways (integration)
activation of Akt direct effects
Akt released from PM
Akt phosphorylates Bad (inactivates)
Bad releases active Bcl2
Active Bcl2 inhibits apoptosis
Unphosphorylated Bad state
promotes cell death (apoptosis) by inhibiting Bcl2 (which suppresses apoptosis)
activation of Akt indirect effects
activated Akt indirectly activates TOR (serine threonine kinase) by phosphorylating and inhibiting TOR suppressor
-caused by binding of extracellular growth factors to RTK receptor
TOR
target of rapamycin
active = cell growth
inactive = autophagy
rapamycin
inhibits TOR, promotes autophagy
anticancer
how to determine binding sites of RTKs and target protein of specific P-Tyr
mutant receptors -replace tyrosine with amino acid that won’t bind target protein (Phe)
introducing a constitutively active Ras rescues a mutation in protein X, but not Y . . . which is upstream of Ras and which is downstream
X is upstream of Ras (activated Ras can recover the signal)
Y is downstream (active Ras cannot recover signal)
