Cell Signaling - Yokomori

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Crosstalk of JAK signaling pway and other pways

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-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

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Tyr Kinase Steps

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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

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FHC: properties

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-Familial hypertrophic cardiomyopathy
-leading cause of sudden cardiac death in young patients
-mutation in sarcomere proteins
->has to maintain higher [Ca2+] -> hypertrophy in cardiomyocytes

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TGFbeta/SMAD pway steps

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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

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PI3 Kinase pathway

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-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

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JAK/STAT steps

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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

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Enzyme-linked receptors and roles

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JAK/STAT plays major role in cytokine signaling for IFN-a, IFN-B, IFN-y and interleukins

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IFN-a/y purposes

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lead to antiviral response and growth restraint in a number of diff't cell types

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reversibility of signaling

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1. covalent protein modification
-(P)
2. Nucleotide exchange
-GTP binding protein

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G protein-coupled

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a.Ligand binding activates a G-protein, which in turn activates/inhibits other enzymes to produce second messengers (i.e. glucagons)

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Receptors with enzymatic activity

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Ligand binding activates the catalytic component of the receptor (i.e. any receptor with Ser/Thr/Tyr kinase, like insulin receptor

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Receptors with enzymatic activity: examples

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(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)

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Mouse models: 4 types & what rely on for getting gene in

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xgenic: nonspecific insertion
k-out, k-in, conditional: Homologous recombination

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Mouse models: endogenous gene

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XG: no change
KO: disrupted
KI: replaced w/ mutant
CK: cond. disrupted (location, tissue, stage of life)

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2 actions of Gq pathway

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PIP2->IP3 and DAG
IP3->ER->releases Calcium
DAG->->PKC

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Cholera

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ADP ribosylates GsAlpha subunit so that it can't hydrolyze GTP
->persistent activation

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Gi

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inhibits Gs pathway
->inhibits adenylyl cyclase->inhib. cAMP

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actetylcholine and G proteins

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non-canonical: beta/gamma does the work and opens the K+channel to relax heart muscle

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Beta 1 receptor

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-heart cells (among other places)
-epineph. binds beta 1 and increases HR
->give beta1 blocker to slow heart down

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Beta 2 receptor

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-in lungs (w/others)
-Epi binds beta 2 receptors in lungs -> relaxes smooth muscle->bronchodilation (for asthma)

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Calmodulin

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activated by binding Ca2+
-alters activity of other enzymes like Ca-calmodulin dependent protein kinase II (CaM Kinase II)

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CaM Kinase II

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-when it binds Ca2+/Calmodulin complex->activates and auto(P)
->sustains itself until dephosphorylated (prolongs response->memory)

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Calcineurin

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-Ser/Thr (P)tase, activated by Ca2+/Calmodulin and Ca2+ alone
-activates NFAT by removing a (P)

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NFAT immune response

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-activated by Calcineurin
-drugs can block (P)tase activity of NFAT and decrease immunity (xplant patients)
-drugs: CSA and FK506

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FHC: drugs

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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])

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Tyrosine Kinase Receptors: properties

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-growth and differentiation
-xmit signal thru Ser/Thr kinases via Ras proteins

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Ras

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-superfamily of GTPases
-mutated in 20-30% of cancers
-Mutant Ras binds GTP but can't hydrolyze it->sustained activation of p-way

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Map Kinase pathway

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1. Activated Ras->Raf Kinase (Map KKK), MEK and others
2. MapK is a Ser/Thr kinase->nucleus->(P) many proteins & xscrip. factors

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Members of Ras Superfamily

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1. Rho/Rac - cytoskeleton organization
2. Rab - membrane trafficking
3. Ran - mitosis and nuclear transport

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Regulation of Ras Signaling

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GAP and SOS

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GAP regulating activities

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-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

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SOS regulating activities

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-is a GEF (guanine nucleotide exchange factor)
-helps enzymes change between GTP and GDP

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Enzyme-linked receptors

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Cytokines and JAK/STAT signaling

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Cytokine signaling

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-involves interleukins (ILs), interferons (IFNs) and colony stimulating factors (CSFs)
-have pleiotropy
-no tyr kinase domains, but recruit PTK to (P) Tyr residues

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JAK-STAT general

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cytokines bind to receptors associated with JAK family

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JAK STAT pathway steps

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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

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STATs: definition

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signal transducers and activators of transcription

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STAT1 deficient mice

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failed to activate genes in response to IFNalpha and IFNgamma

->high sensitivity to viral and microbial infections

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STAT4 deficient mice

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had lymphocytes that were unable to fight infections

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TGF beta: properties

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-regulates developmental processes: differentiation, skeletal morphogenesis and skin formation
-binds heteromeric cell surface receptor complexes w/Ser/Thr kinases

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TGF beta examples

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activins and bone morphogenic proteins (BMPs)

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TGF beta receptor types

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Type I and II

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SMAD: properties

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-located in cell
-xmits signal from extracellular TGF beta

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Pancreatic cancer

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-SMAD 4 suppresses tumors
-loss of SMAD 4 results in pancreatic cancers

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Marfan Syndrome

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-mutations in Type II receptors
-autosomal dominant
-disorder of fibrous connective tissue
-affects skeletal and cardiovascular systems