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45 Cards in this Set

  • Front
  • Back
Crosstalk of JAK signaling pway and other pways
-JAK xtalks w/ MAP Kinase pway thru Ras and Raf
-JAK has substrates besides STATs
-JAK can associate w/ other non-receptor Tyr kinases
-STATs can interact w/ other txn factors
Tyr Kinase Steps
1. Ligand->homodimer->auto(P)@Tyr
2. (P)Tyr is docking site for GRB2 adaptor proteins
3. GRB2 complexes w/SOS->facilitates RasGDP to RasGTP (slow, add GAP to speed up)
4. RasGTP -> Map Kinase and PI3 kinase p-ways
FHC: properties
-Familial hypertrophic cardiomyopathy
-leading cause of sudden cardiac death in young patients
-mutation in sarcomere proteins
->has to maintain higher [Ca2+] -> hypertrophy in cardiomyocytes
TGFbeta/SMAD pway steps
1. ligand->Type II receptor
2. Type I receptor joins complex and (P) by T-II receptor
3. (P)T-I receptor (P)ates "Pathway-Restricted SMADs
4. (P) of SMADs causes dimerization w/SMAD 4->nucleus ->txn activity
5. Inhibitory SMADs (6&7) block activation of p-way restricted SMADs
PI3 Kinase pathway
-a lipid kinase
-activated in proliferation, differentiation, cell survival and cytoskeletal reorg.
-activated by Ras-independent and dependent p-ways
-PI3 (P) PI lipids->become binding sites for various kinases
JAK/STAT steps
1. cytokine binding induces receptor chains to oligomerize or reorient in preformed oligomer
2. binding of ligand and conformation change brings cytoplasmic kinases close-> (P) eachother
3. JAKs (P) Tyr residue on STATs, causing them to dissociate from receptor
4. (P)-STATs dimerize-->nucleus & bind DNA response elements
Enzyme-linked receptors and roles
JAK/STAT plays major role in cytokine signaling for IFN-a, IFN-B, IFN-y and interleukins
IFN-a/y purposes
lead to antiviral response and growth restraint in a number of diff't cell types
reversibility of signaling
1. covalent protein modification
2. Nucleotide exchange
-GTP binding protein
G protein-coupled
a.Ligand binding activates a G-protein, which in turn activates/inhibits other enzymes to produce second messengers (i.e. glucagons)
Receptors with enzymatic activity
Ligand binding activates the catalytic component of the receptor (i.e. any receptor with Ser/Thr/Tyr kinase, like insulin receptor
Receptors with enzymatic activity: examples
(tyrosine-kinase)-linked receptors: ligand binding stimulates formation of a dimeric receptor that interacts on cytosolic protein-tyrosine kinases (i.e. receptors for cytokines, interferons and human GF)
Mouse models: 4 types & what rely on for getting gene in
xgenic: nonspecific insertion
k-out, k-in, conditional: Homologous recombination
Mouse models: endogenous gene
XG: no change
KO: disrupted
KI: replaced w/ mutant
CK: cond. disrupted (location, tissue, stage of life)
2 actions of Gq pathway
PIP2->IP3 and DAG
IP3->ER->releases Calcium
ADP ribosylates GsAlpha subunit so that it can't hydrolyze GTP
->persistent activation
inhibits Gs pathway
->inhibits adenylyl cyclase->inhib. cAMP
actetylcholine and G proteins
non-canonical: beta/gamma does the work and opens the K+channel to relax heart muscle
Beta 1 receptor
-heart cells (among other places)
-epineph. binds beta 1 and increases HR
->give beta1 blocker to slow heart down
Beta 2 receptor
-in lungs (w/others)
-Epi binds beta 2 receptors in lungs -> relaxes smooth muscle->bronchodilation (for asthma)
activated by binding Ca2+
-alters activity of other enzymes like Ca-calmodulin dependent protein kinase II (CaM Kinase II)
CaM Kinase II
-when it binds Ca2+/Calmodulin complex->activates and auto(P)
->sustains itself until dephosphorylated (prolongs response->memory)
-Ser/Thr (P)tase, activated by Ca2+/Calmodulin and Ca2+ alone
-activates NFAT by removing a (P)
NFAT immune response
-activated by Calcineurin
-drugs can block (P)tase activity of NFAT and decrease immunity (xplant patients)
-drugs: CSA and FK506
FHC: drugs
CSA and FK506 won't help because can't maintain high enough concentrations in heart cells w/o thrashing immune systems (have a higher [NFAT])
Tyrosine Kinase Receptors: properties
-growth and differentiation
-xmit signal thru Ser/Thr kinases via Ras proteins
-superfamily of GTPases
-mutated in 20-30% of cancers
-Mutant Ras binds GTP but can't hydrolyze it->sustained activation of p-way
Map Kinase pathway
1. Activated Ras->Raf Kinase (Map KKK), MEK and others
2. MapK is a Ser/Thr kinase->nucleus->(P) many proteins & xscrip. factors
Members of Ras Superfamily
1. Rho/Rac - cytoskeleton organization
2. Rab - membrane trafficking
3. Ran - mitosis and nuclear transport
Regulation of Ras Signaling
GAP regulating activities
-Ras-GTPases are slow
-GAP accelerates GTPases by 10^5
-homolog of it is RGS->used to accelerate G protein alpha subunit by 100 fold
SOS regulating activities
-is a GEF (guanine nucleotide exchange factor)
-helps enzymes change between GTP and GDP
Enzyme-linked receptors
Cytokines and JAK/STAT signaling
Cytokine signaling
-involves interleukins (ILs), interferons (IFNs) and colony stimulating factors (CSFs)
-have pleiotropy
-no tyr kinase domains, but recruit PTK to (P) Tyr residues
JAK-STAT general
cytokines bind to receptors associated with JAK family
JAK STAT pathway steps
1. ligand binds JAK kinase, activated by auto(P)
2. (P)Tyr residue on receptor->binding sites for STATs
3. after recuitment, STATs (P) by JAK
4. STATs leave, dimerize->nucleus->become xscrip factors
STATs: definition
signal transducers and activators of transcription
STAT1 deficient mice
failed to activate genes in response to IFNalpha and IFNgamma

->high sensitivity to viral and microbial infections
STAT4 deficient mice
had lymphocytes that were unable to fight infections
TGF beta: properties
-regulates developmental processes: differentiation, skeletal morphogenesis and skin formation
-binds heteromeric cell surface receptor complexes w/Ser/Thr kinases
TGF beta examples
activins and bone morphogenic proteins (BMPs)
TGF beta receptor types
Type I and II
SMAD: properties
-located in cell
-xmits signal from extracellular TGF beta
Pancreatic cancer
-SMAD 4 suppresses tumors
-loss of SMAD 4 results in pancreatic cancers
Marfan Syndrome
-mutations in Type II receptors
-autosomal dominant
-disorder of fibrous connective tissue
-affects skeletal and cardiovascular systems