Cell Signaling Flashcards
basic template for cell signaling
primary transduction, relay, amplification, divergence to multiple targets
four methods of intercellular communication
endocrine - long distance such as insulin or erythropoeitin
paracrine - signal from one cell to a nehgboring cell
autocrine - when a cell produces a substance that acts on itself
juxtacrine - when a cell sends a signal to a neighbor
three mothods of intermolecular communication
2nd messengers
phosphorylation
direct contact
switch and timer models
switch - signaling by phosphorylation
timer - signaling by GTP-binding protein
two major calsses of receptors
cell surface receptors and intracellular receptors
nuclear receptors
ligands pass through membrane and binds to receptor in cytoplasm, which goes to the nucleus and activates transcription
ex. cortisol meade by adrenals during stress
membrane receptors
ion channel-linked receptors - facilitate transport of ions in response to ligand binding (ex. acetylcholine receptor)
G-protein-linked receptors - seven transmebrane helicies, associated with a G-protein (ex. adrenergic receptor)
enzyme-linked receptors - receptor itself has eznymatic functions (ex. tyrosine kinases)
other receptors don’t have enzymatic functions or are multimeric
cytokine receptors
don’t have enzymatic activity buy but activates other molecules that phosphorylate the receptor and provide adaptor sites for downtream elements
notch signaling
juxtacrine receptor where ligand is on once cell and receptor is on another
ligand interacts with receptor and activates a protease, cleaving part of the receptor, taking it to the nucleus wher eit affects transcription
second messengers
cAMP, IP3, DG, Ca2+
diffuse throughout the cell for singal amplification
cross-talk and fine tuning
rapidly degraded or consumed
receptor binding - saturation, affinity, dose-response
receptors can be saturated depending on ligand concentration
the rate of saturation depends oin on the affinity
there are usually a lot more recepotrs present than necessary for strong signals
can control the response of the cell based on how many receptors are present
recycling of receptors
receptors that are used get internalized and sent to endosomes, where they are then degraded in lysosomes or recycled to the cell membrane
receptor desnsitization
in the case of G protein receptors, kinases (GRK) phosphorylate the receptor, leading to beta-arresin to bind
this prevents ligand binding and promotes internalization for recycling or degradation
types of G proteins
large G proteins - G(s), G(i), Golf, Ggust
small G proteins - Ras, Rho, Cdc42, Rac
other G proteins - dynamin, tubulin
about 1000 types of receptors in the genomes, receptors can be modified to recognize ligands, epending on what parts ar phosphorylated
regulators of G proteins
GTP/GDP cycle, inactive state bound to GDP, activated state bound to GTP
GTP exchange factors GEF, GDI)
GTPases (GAP), hydrolysis of the terminal phosphate group
heterotrimeric G proteins
composed of alpha, beta, and gamma subunits
alpha subunits bind to guanine nucleotides, and the bta-gamma subunits keep conformations in check
GDP exchange for GTP cause them to dissociate and relay signals
the GTP wills tay active for about fifteen seconds before inactivation occurs
Gs
stimulates adenylate cyclase in response to beta-adrenergic, glucagon, PTH
Gi
inhibits adenylate cyclases in response to acetylcholine, alpha-adrenergic
Gt
activates cGMP phosphodiesterases in response to light
Gq
activates phospholipase C in response to chemoattractants and thrombin
G13
activates tyrosin kinases in response to thrombin
Ggust
activates cNMP phosphodiesterase in response to taste signals
Golf
activates adenylate cyclases in response to olfactor signals
phosphatidylinositol signaling
G protein activation leads to activated phospholipase C
this cleaves inositol phospholipid to creat inositol-1,4,5-triphosphate and diacylglycerol
IP3 activates calcium channels in the ER which leads to calmodulin and PKC activation
DG leads to activation of PKC
cyclic AMP signaling
activation of G protein leads to activation of cyclic AMP, which turns ATP into cAMP
cAMP then activates PKA, which phosphorylates proteins such as CREB in the nucleus and promotes transcription
cholera pathway
cholera toxin adds ADP-ribose to Gsalpha, making it slow to hydrolyze the GTP
this increases PKA activation, which leads to a phosphorylated chloride channel that is always open
this leads to profuse, watery, life-threatening diarrhea
pertussis pathway
leads to the prolonged activation of Gialpha, locking it in the inactivated state, which prevents it from inhibitiing adenylate cyclase
this leads to the resulting cough
Ras and Ras-related GTPases
post-translational modification include farnesylation, geranyl geranylation, which allows it to anchro to the plasma membrane
relay switch that activates pathways, turned on by switching its GDP to a GTP, can then interact with other molecules and stimulate pathways such as the MAPK pathways
GTP/GDP recycling of G proteins
GEF/GAP proteins control the activity of many G proteins
GEF - exchanges GDP for GTP
GAP - GTPases that exchange GTP for GDP
Rac/Rho/Cdc42 and Rab
Rac/Rho/Cdc42 = cytoskeletal reorganization
Rab = vesicle trafficking
receptor and non receptor tyrosine kinases
activation loop phophorylation
dimerization and trans-phosphorylation of tyrosine molecules
responds to many growth factors and comes in a divers range of structures
usually have two subunits split apart
regulation of Src kinase
viral kinase, phosphotyrosine residue at the C terminus of tyrosine kinases, recognized by the SH2 domain
An SH3 domain that recognizes a proline rich region, conformational impossibility
As a result of a phosphatase, phosphate group gets cleaved and the kinase becomes active after a conformational change
regulation of tyrosine kinases
dissociation of a negative regulatory subunit
displacement of a psudosubstrate motif
displacement of a negative regulatory domain
association with positive regulatory factor
phosphorylation-induced conformational change
activation via proteolytic cleavage
tethering to membrane-associated factors or lipids
translocation to the nucleus
insulin receptor
activation by binding to insulin causes phosphorylation of the tail
this attracts docking protein IRS, hwich has domains recognized by other SH2 and PTB domain proteins, leading to downstream activation pathways
chronic myeloid leukemia
caused by a 9;22 translocation, which produces Bcr-Abl
this hybrid gene is always on, leading to proliferation of mature and immature white blood cells
