Signal Transduction 3 Flashcards
receptors basic categories
1-Ligand gated channels
2-Plasma membrane receptors
—-linked to g proteins
—-linked to protein kinase
3-Nuclear protein
linked to protein kinase (plasma membrane)
RTK–Receptor Tyrosine Kinases
GPCR regulate
Shorter term metabolic changes
RTK regulate
differentiation, cell division, survival
signal that stimulate dividing cells is
growth factor
many growth factor share a common theme
1-growth factor binding result in dimerization of receptors
2-trans-auto-phosphorylate of cytoplasmic domain does not phosphorylate itself, phosphorylate the neighbor
3-cytoplasmic signalling activated by binding to phosphorylated tyrosine
cytoplasimic signalling molecules associate with receptors by
SH2 and PTB domains
SH2
amino acids chains contain binding pocket that interact with pTyr
Adaptors
act as linkers enabling
contain SH2/PTB domain
Additional protein-protein interaction
Adaptors with SH2 domain
GRB2 bind to RTK
SH3 domain associated with Sos
Adaptor with PTB domain
IRS bind with RTK
lead to phosphorylation of IRS tyrosine
pTyr act as scaffolding for SH@ enzymes
Effectors
1- STAT family
2- Signalling enzymes with SH2 Domains wich can directly bind to RTK
STAT family
SH2 domain STAT bind to RTK, phosphrylate tyrosine in STAT, allow STAT dmierize, forming functional tanscription factor, trnaslocate to nucleus
signalling enzyme (with Sh2 doamin and ability to bind with RTK
protein kinases
shp2
plc
GAPs
signalling enzyme mechanism
1- recruitment of enzyme
2-binding of pTyr can result in conformational changes in catalytic domain
3- phosphorylation of enzyme can increase/decrease catalytic activity
Termination
RTK doesn’t require Arrestin (GPCR need arrestin)
they have short motif interacting with AP2
After binding with AP2: (3outcomes)
1- can resume within endosome
2- traficked by lysosome for degradation
3- returned to cell surface RE-sensitization
G protein act as —- and —- to regulate cellular events
switches and timers
Ras
small monomeric G protein s
accessory protein help switch ras on/off
GAP: GTP hydrolysis
GDI: inhibitor–GDP can’t reactivate
GEF: activate GDP to GTP
activated G protein is —- based
time
RAs-MAP
1-EGF to RTK extracellular domain
2-dimerize
3- trans auto phosphorylate
4- GRB2 high affinity for pTyr
5-GRB2 assocaite with Sos
6-Sos is RasGEF
7- binding GRB2 to pTyr, brings Sos near Ras, allowing GDP to be replaced by GTP
8- Ras-GTP has high affinity for MAPKKK
9- MAPKKK phosphrylate Serine and Threonine in MAPKK
10- MAPKK phosphorylate MAPK
11- Activated MAPK can phosphorylate over 160 proteins
12- Activate genes in cell proliferation
multiple pathways can be activated at the same time
Diverngence
RAS when in active state should be inactivate to —-
avoid constitutional stimulation
RAS inactivate by
RasGAP
Ras extra mutation can lead to
cancer
different members of MAP kinase family can elicit different cellular pathways via
having different MAPKKK/MAPKK/MAPK activate
how many different MAP family we have
14 MAPKKK
7 mAPKK
13MAPK
In signal transduction, linear pathway does not happen instead there is
conergence/divegence
Nuclear Receptors
Soluble protein that mediate action of steroid hormones
–lipid signaling molecule which can pass easily through plasma membrane
—-receptor itself is an effector(no cascade)
Nuclear receptors have two main domain
1- LIganid binding domain
2- DNA binding domain
steroid receptors act by binding
HRE (hormone response element)
Binding to HRE can be
enhanced or repressed gene expression
DNA binding doamin is
two zinc-finger motifs
starting material for synthesis steroid hormines
cholesterool
cortisol is
glucocorticoids
aldesterone is
mineralcorticoids
corstisol pathway
1- enter the target cell
2- bind to glucocorticoid receptor
3-receptor changes conformation of the protein
4-expose nuclear localization signal
5- enter nucleus
6- activate/inhibit transcription
Ligand gated channels
channel scan be opened/closed by binding of a ligand
allow passage of specific ions
ligand can be neurotransmitters
Ligand gated activation
1-AP moves down a neuron to NMJ
2-AP opens voltage-gated Ca channels
3- elevated Ca conc. triggers ACh exocytosis
4-ACh will open ligand-gated Na channels
5- Na flows in
6- AP moves along membrane into t-tubules
7- AP activate voltage-gated CA channels on SR
8- Ca is released into cytoplasm and act as second messenger
9-Troponin C undergo conformational change
10- relieving tropomyosin blockage of actin-myosin binding site
11- myosin can now cause interaction
calcium-induced-clacium-released
