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96 Cards in this Set
- Front
- Back
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adenyl cyclase |
effector protein activated and inhibited by GPCRs AMP--> cAMP |
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ligands that can activate GPCR-cAMP pathway |
stimulatory G. prot. receptor binding ligands: epinephrine, ACTh, glucagon |
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ligands that dec./ inhibit GPCR-cAMP signal |
bind to GPCR that have inhibtry alpha subunits adenosine, PGE1 |
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cholera |
CHOLERA: - diarrhea, excess water loss= death - toxin enters enterocytes (small intestine) through GM1 RECEPTOR - activates GPCR (alpha-s)--> stimulates adenyl cyclase--> cAMP constitutively expressed--> PKA--> CFTR -CFTR overstimulated: lots of Cl- leaving cell --> causes Na+ and H2O to leave cell **people hetero. for CFTR mutation= survive cholera |
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receptor for cholera toxin |
G1 (ganglioside) receptor |
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pertussis toxin |
whooping cough ciliated epithelial cells in lungs toxin =endocytosed (no receptor) inhibits GPCR alpha (i) that regulates GPCR alpha (s) mass activation of adenyl cyclase--> cAMP--> PKA--> CFTR--> Na+, Cl-, H2O in lungs inc. mucous in lungs; constantly trying to cough out |
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parts of PKA |
activated by cAMP 2 regulatory subunits --> both have 2 cAMP binding sites : CNB-A , CNB-B **cAMP @CNB-B first 2 catalytic subunits --> dissociate and go into nuc. once cAMP binds to reg. subunits |
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second messengers |
cAMP-->PKA cGMP--> PKG DAG--> PKC IP3 --> Ca2+ channel in ER |
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PKA roles |
PROTEIN KINASE A activated by cAMP phosphorylates genes, and proteins different roles in different cells --> inhibitory and excitatory phosphorylation |
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PKG role |
protein kinase G activated by cGMP opens cation channels in ROD CELLS |
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cAMP responses |
glucose liberation --> glycogen to glucose conversion (skeletal) --> inhibit glycogen synthesis, inc. gluconeogensis, inc. a.a. uptake (liver) heart muscle contraction vasoconstriction (NO also involved) |
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metabolism when no cAMP |
**no cAMP= no adenyl cyclase activity no cAMP= no PKA activity phosphoprotein phosphatase= ACTIVE (takes off P) --> INACTIVATES GPK (glycogen phosphorylase kinase) |
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GPK |
glycogen phosphorylase kinase active form: P-GPK activates GP |
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GP |
glycogen phosphorylase active form: P-GP glycogen--> glucose-1 |
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PP |
phosphoprotein phosphatase active form: PP activates GS inhibits GPK and GP |
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IP |
inhibitory phosphatase active form: IP-P inhibits PP |
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GS |
glycogen synthesis active as GS --> when no cAMP regulated by PP |
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whats active and inactive when cAMP present |
cAMP= increased metabolism active: GPK GP IP--> inactivates PP inactive: PP GS activation/ inactivation by PKA |
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whats active /inactive when no cAMP |
active: PP -->GS inactive: GPK, GP (b/c of PP) |
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CREB protein |
cAMP response element binding protein transcription factor that binds to CRE (as dimer) activated by PKA IN NUCLEUS |
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CRE |
cAMP response element sequence in CREB TGACGTCA usually in promotor |
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phospholipase C |
effector protein activated by GPCR seconder messengers IP3 and DAG |
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PIP2 |
breaks into IP3 and DAG when PLC activated |
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IP3 |
opens Ca2+ membrane in ER membrane |
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ca2+ and PLC-GPCR pathway |
released by binding of IP3 to ER channel activates PKC and calmodulin |
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PKC |
TRANSLOCATED when Ca2+ binds goes to PM and interacts w/ DAG= ACTIVATED activates MAPK |
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PLC gamma |
not activated by GPCR activated by PTK RECEPTORS --> still activates MAPK |
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Ca2+ binding to calmodulin |
calm. /Ca2+: synthesizes NO shortlived gas--> muscle cell NO receptor--> cGMP--> PKG--> relaxes muscle cell |
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Ca2+ binding to PKC |
PKC to pM --> activated by DAG--> MAPK activation |
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NO receptor |
guanylate cyclase in muscle cell when bound to NO: AMP-->gAMP |
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angina |
chest pain b/c of ischemia in heart muscle--> lack of oxygen supply smooth muscle NOT RELAXING |
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VIAGARA |
increases blood flow by constant muscle relaxation GPCR/ PLC / Ca2+/calmodulin pathway NOT REGULATED: NO in corpus cavernosum inhibits PDE-5 --> turns cGMP back to GMP inc. blood flow: no new blood :cells dying b/c no oxygen |
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priapism |
persistant and painfull erection viagara (inhibition of PDE5) |
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CYANOPSIA |
blue tint viagara (PDE5 inhibited) |
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PDE5 |
turns cGMP--> GMP regulates muscle relaxation after NO receptor produces lots of cGMP |
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RTKs |
single membrane alpha helix cytoplasmic domain= intrinsic TYROSINE kinase activity activated when receptor dimerizes |
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Ras |
GTP switch protein active w/ GTP --GEF for Ras: sos functions to recruite Raf to PM |
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RTK pathways |
can be coupled to G protein--> eventual activation of transcription factor direct activation of transcription factor |
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adaptor proteins |
SH2 PTB dock on phosphotyrosines (P-tyrosine residues on PTK cytoplasmic domain) |
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docking site for adaptor proteins |
phosphorylated tyrosine residues on cytoplamsic RTK domain **autophosphorylation dimerization (bc of ligand binding) leads to high kinase activity |
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SH2 |
domain of adapter proteins that bind to P-tyr of RTKs in 100 human proteins |
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PTB |
domain of adapter proteins that binds to P-Tyr of cytoplasmic RTKs |
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src protein |
Src- sarcroloma first oncogene discovered SH2, SH3 and kinase domain constitutively active src= active kinase= pathways that lead to uncontrolled cell growth |
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c-src v. v-src |
v-src (rous virus) is constantly active **missing C-terminal a.a that is regulatory --in c.-src: phosph. of this a.a.= inhibits src protein kinase activity -virus= constantly on = oncogenic |
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common Ras mutation |
no GTP hydrolysis = no Raf activation 20-30% human cancers |
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GEF for Ras |
Sos |
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how is Ras activated |
ras= monomeric g-prot. activated through RTK and adapter proteins --> sos RTK/ GF --> GRB2 (adaptor): SH2@RTK, SH3@sos--> sos(GEF)/ Ras--> Ras+GTP= dissociation Ras+GTP--> Ras/Raf--> Ras hydrolysis: Raf dissociation--> Raf (MAPKKK) -->MEK (MAPKK)--> MAPK --> MAP --> transcription factors |
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sos |
binds to SH3 of GRB (adaptor) also binds to Ras and switches GDP --> GDP |
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raf |
MAPKKK activated by Ras and brought to PM dissociates from Ras when Ras hydrolyzes GTP activates MEK phosphorylated S , T residues |
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MEK |
MAPKK activated by raf activates MAPK phosphorylates S, Y, T residues |
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MAPK |
activated by MEK phosphorylates S / T residues |
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ERK |
another name for MAPK extracellular signal-regulated kinase |
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neu oncoprotein |
mutation in her2 receptor dimerizes w/o ligand overactivation of RTK |
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ErbB oncoprotein |
deletion of extracellular LBD in EGF receptor overactivation of RTK |
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her2 |
PTK oncogene protein |
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EGF receptor |
RTK oncogene protein |
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NF1 |
tumor suppressor gene GAP protein hydrolyzes GTP in Ras and TURNS OFF RAS regulates cell cycle /growth |
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mutation in NF1 |
recessive loss of function mutaiton NF1 not functioning no GTP hydrolysis in ras RAS= constitively activating Raf (---->MAP+++) |
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overactivity of which proteins in RTK/MAP pathway =cancer? |
Ras (GRB2, SOS) RTK Raf MEK MAPK **constutive activation= mutation |
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HER |
human epidermal growth factor receptors 4 diff types: HER1/2/3/4 **RTKs usually ONLY HER1 HOMODIMERIZES *breast cancers (100X more HER2 expression) |
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HER2 |
usually doesn't homodimerizes -usually dimerizes w/ 1/3/4 -mutation= homodimerization w/ low levels of EGF **targetted by mAB : HERCEPTIN |
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HERCEPTIN |
monoclonal antibody that dec. HER2 activity **passive immunity can be provided 1. prevents dimer formation 2. prevents EGF from binding 3. prevents cleaving of HER2's extracellular domain (would normally= overactivation of HER2 w/o ligand) 4. binds her2 and signals immune cells to kill 5. interferes/ reduces mitogenic signalling of HER2 receptor 6. Ab binding triggers endocytosis of receptor (receptor--> lysosome) |
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apoptosis |
chromosome condenses apoptotic bodies recog. by phagocytes nucleases activated |
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necrosis |
cell spews insides IMMUNE INFLAMM. RESPONSE TOXIC TO NEIGHBOURING CELLS |
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nucleases |
activated during apoptosis cut every 200bps |
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c. elegans |
male: 1031 cells hermaphrodite: 959 cells genomes= full sequenced all cells= mapped 1mm long |
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cells in newborn c. elegans |
1090 |
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technology to study c. elegans |
DIC Dead cells= HIGHLY REFRACTILE -->little blots |
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mutations effecting apoptosis in c. elegans |
mutations to ced genes CED3 & CED4 PREVENT APOPTOSIS |
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ced9 mutation |
ALL CELLS DIE BY APOPTOSIS anti-apoptotic adult doesnt develop- death during embryogenesis resembles bcl-2 in mammals |
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ced 3 mutation |
no apoptosis c. elegans ced3= caspase sim. to caspase 9 |
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ced 4 mutation |
in c. elegans no apoptosis extra cells sim function to apaf-1 in mammals (forms apoptosome) |
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caspases |
cysteine-dependent, asparte- directed made as procaspases need to be CLEAVED to be activated initiator and effector caspases ROLES IN APOPTOSIS: DNA Fragmentation nucleus fragmentation (act on nuc. lamins) cytoskeleton proteins golgi fragmentation |
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initiator caspase |
activated by DIMERIZATION Cleave effector procaspases--> active effector caspases |
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effector caspases |
EXECUTIONERS cleave other proteins in cell to trigger APOPTOSIS |
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cleaving nucleus lamins |
done by effector caspases nuc. lamins normally =proteins that stabilize nuc. cytoskeleton cleaving= fragmentation of nucleus |
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apoptosome |
1.4 megadalton wheel of death made up of: apaf-1 caspase 9 cytochrome c --> comes from mito. |
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bax |
sim to bak makes up oligo. channel in mito. membrane allows cyto. c to exit mito. channel forming inhibited by bcl2, bcl-xl proteins |
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anti apoptotic proteins |
BCL2 family in mammals BH1,2,3,4 and TM domains ced9 in c. elegans |
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pro-apoptotic proteins |
Bax/ bak --> form mito. channel -->BH1, 2, 3, TM Domains Bad/ bid/ bik --> inhibit anti-apop. : bcl2 --> BH3 only domains+ hydrophobic domain |
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bcl-2 family |
first apoptosis related gene isolated b cell lymphoma inhibit apoptosis capabale of oliogmeric interactions Bcl-2 homology domains: BH1,2,3,4 -->expressed in ~20 proteins |
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bh1,2,3 and TM |
pro-apoptotic proteins bax, bak |
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bh1, 2, 3, 4, and TM |
bcl-2, bcl-xL, Bcl-w, Mcl-1, A1 inhibit bax pro suvival anti apoptotic |
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bh3, hydrophobic domain |
PRO apoptotic anti survival bad, bid, bik inhibit bcl-2 (allows bax/bak to form pore) |
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apaf-1 |
apoptotic protease activating factor-1 monomer when not bound to cyto.c activated when bound to cyto. c --> forms disk shaped HEPTAMER --> belly attracts caspase-9 |
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caspase 9 |
initiator protein involved in formation of apoptosome attracted to belly once heptamer of apaf-1/cyto.c formed DIMERIZES @BELLY can activate effector caspases ced4 in c.elegans |
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trophic factors and apoptosis pathway |
trophic factors--> RTKs--> kinases--> bad phosphorylation = bad/14-3-3 interaction: inhibits bad |
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14-3-3 |
inhibitor proteins inhibits bad when bad=phosphorylated |
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phosphorylated bad |
interacts w/ 14-3-3 phosph. by kinase thats activated by trophic factor/ RTK activity |
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activated bad |
activated when trophic factor w/drawal bad NOT phosph. TRYING TO START APOPTOSIS: free to inhibit bcl-2 |
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intrinsic apoptosis pathway |
trophic factor w/drawal |
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extrinsic apoptosis pathway |
death signals from other cells TNF alpha ( lipid anchored to PM) Fas (transmembrane ligand) |
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caspase 8 |
initiator caspase --dimerizes when activated - cleaves bid |
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bid |
BH3 only domain (& hydrophobic domain) effector caspase cleaved by caspase 8--> t-bid t-bid inhibits BCL-2 |
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TNF receptor |
binds TNF alpha mediates cell-cell contact "death receptor" --> binding w/ TNF alpha= casp. 8 activated |
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TNF alpha |
death signal lipid-anchored to PM of other cells |
