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16 Cards in this Set
- Front
- Back
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Growth Factors and RTKs
-dimerization and cross-phosphorylation -RTK activation -SH2 domains |
1. RTKs have to dimerize in the presence of GF before ligand can bind (dimer lays horizontally and antiparellel on receptors)
2. dimerization/binding of GF leads to autophosphorylation= 2 RTK chains cross-phosphorylate one another -phosphorylation of catayltic domain= increase PK activity -phosphorylation outside catalytic domain= creates binding sites for proteins that transmit signal downstream -Downstream signaling molecules have SH2 domains that bind to activated Phosphotyrosine peptides. -SH2= Src homology 2 domain |
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Classes of RTKs
1. EGF receptor 2. insulin receptor 3. PDGF receptor |
common: all have intracellular tyrosine kinase domain near C terminus; all are single pass membrane proteins; binding of ligand activates the kinase domains that causes phosphorylation of receptors and target proteins that propagate signal
1. EGF receptor: extracellular domain is Cys-rich 2. insulin receptor: seperate alpha and beta subunits; beta subunit is the membrane protein, alpha subunit is completely extracellular. Alpha and beta subunits form disulfide bonds to bind and then form a dimer with another alpha-beta dimer with disulfide bonds b/t the two alpha subunits 3. PDGF receptor: extracellular Ig-like domains and split TK domain that allows multiple downstream signal proteins to bind simultaneously -binds to PLC, PI3 Kinase, and GAPs |
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RTK activation of PI3-Kinase signaling cascade
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General outline:
Survival signal (instead of GF) binds and RTK is phosphorylated. PI3-Kinase binds to phosphotyrosines, PIP2 is phosphorylated to PIP3. Akt activated/phosphorylated by PDK. Active Akt can activate Bad and Caspase-9 for cell survival, TF for gene expression, and GSK-3 for metabolism and protein synth 1. PI3K's SH2 domain binds to RTK receptor and takes a phosphate, then phosphorylates PIP2 to make PIP3 2. Akt and PDK1 bind to PIP3 molecules (embedded in membrane). 3. PDK1 and mTOR (from mTORC2 complex) each phosphorylate and ACTIVATE akt 4. activated Akt activates TF of the FOXO family and inhibits Bad and GSK-3 |
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mTOR pathway
-main function 1. -what happens in the presence of GF 2. -what happens if there is low energy |
-a kinase complex that couples control of protein synthesis with availibility of GF, nutrients, and energy
mTORC1 phosphorylates 2 targets that regulate protein synthesis -First path: mTORC1 activates S6 kinase controls translation phosphorylates Ribosomal protein S6 -Second path: activation of eIF4E binding protein interacts with its initiating factor which binds to the 5' cap of mRNA to regulate translation 1. In the presence of growth factors: -GF binds to RTK, activates PI3K, and Akt is activated -Akt inhibits TSC complex (GTPase activating protein), which depresses Rheb (GTP-binding protein) which permits increases in translation by activating mTOR 2. If there is low energy: AMPK becomes activated (no GF of Akt activation), this activates TSC complex and Rheb and leads to mTORC1 inhibition and decreases translation |
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PI3K activation: GLUT4 response to insulin
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-GLUT4 hangs around in vesicle storage in muscle and fat cells until there is insulin binds to its receptor
Process of bringing GLUT4 to the membrane... -insulin binds to its receptor in dimer form -activated receptor phosphorylates/activates IRS-1 (soluble mediator) -IRS binds to p85 regulatory subunit of PI3K. This activates the p110 subunit that converts PIP2 to PIP3 -PIP3 binds to PKB and signals PKD1 to phosphorylate PKB -activated PKB phosphorylates other targets (Akt and PKC) to stimulate GLUT4 to be expressed on the PM -GLUT4 on PM: facilitiative diffusion of glc into cells, rapidly sent to glycolysis by being rapidly phosphorylated by hexokinase, this keeps glc in the cell to maintain conc. gradient to keep it moving in |
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FOXO function
1. In absence of GF 2. in presence of GF |
FOXO= TF, when GF not present it travels to the nucleus to stimulate transcription of genes that inhibit cell proliferation or induce cell death
2. when GF is present: GF binds to RTK, PI3K activated and phosphorylates/activates Akt -Akt phosphorylates FOXO and a cytoplasmic chaperone binds to the P's on the FOXO and keep it from entering the nucleus to bind DNA. -FOXO induced genes are not expressed, and cell is able to proliferate/survive |
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PI3K signaling and oncogenes
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Tumor developes b/c failure to undergo programmed cell death
-PI3K and Akt act as oncogenes in retroviruses and human tumors -GF binds to GF receptor, PI3K phosphorylates PIP2 to PIP3 which activates Akt; Akt regulates Bad and FOXO; FOXO activates BIM; BIM and Bad activated **Bcl-2 (regulates programmed celll death); Bcl-2 inhibits cyt c release from the mitochondria which normally activate caspase that causes cell death. |
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RTK activation of PLC gamma
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PLC gamma has a SH2 domain that interacts with phosphorylated RTKs
-activated PLC stimulates hydrolysis of PIP2 to IP3 + DAG. -DAG stays in membrane and activates protein serine/threonine kinases of the protein kinase C family -IP3 goes to ER to signal Ca2+ release -Ca2+ conc increase in cytosol affects activity of several proteins like kinases and phosphatases (Ca2+/calmodulin dependent protein kinase) |
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Crigler Najjar syndrome (congenital unconjugated hyperbilirubinemia)
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severe jaundice in neonate
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RTK-Ras-GAP (Raf) activation of MAPK pathway
-characteristics of MAPK -signaling pathway starting with RTK -Alt route: RTK directly activates Ras-GAP |
characteristics of MAPK:
-mitogen activated protein kinases -protein-serine/threonine kinases -highly conserved -belong to ERK family (extracellular signal-regulated kinase) -way downstream from receptor; activated by two upstream PKs coupled with GF receptors by the Ras GTP-binding protein Pathway: GF binds, RTK phosphorylated, Grb2 binds to phosphate groups, Grb2 bound to SOS (GEF) binds to Ras-GDP, SOS which EXHANGES whole molecule of GDP on Ras with GTP, Ras-GTP goes to Raf and activates it (stays on PM). Raf is a GTPase Activating protein (GAP); it cleaves off a phosphate; Raf starts kinase cascade by ERK activation (and Ras-GDP recycled). MEK activated by Raf, MEK activates ERK, ERK phosphorylates nuclear and cytoplasmic proteins *some ERKs can go to nucleus to change rate of transcription by phosphorylating TF Alt. pathway: -RTK directly activates Ras (without SOS) from SH2-mediated interaction |
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ERK and transcriptional activation
-function of ERK -players involved -purpose of activation |
TFs SRF and ELK1 bind to SRE (serum response element) on DNA and activate transcription
-ERK domes in to nucleus and phosphorylates ELK1 to activate it -primary repsonse to GF stimulation is rapid transcriptional induction of **immediate-early genes -signal for cell proliferation, differentiation, or survival |
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Different mammialian MAPKs, and how they are organized in the cell
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ERK used in response to GF for proliferation, differentiation, and survival
-JNK and p38 MAPKs are used in response to inflammatory cytokines and cell stress to signal inflammation or cell death -specificity of MAPK maintained by maintaining physical association on scaffold proteins (KSR) -KSR is a protein that binds Raf MEK and ERK and holds them in order in place in a signaling cassette |
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Mutations on Ras
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inhibits GTP hydrolysis by Ras so Ras remains continually active even without GF stimulation
-drives proliferation of cancer cells |
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oncogenes and the ERK pathway
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erbB-2 proto-oncogene encodes a RTK (ErbB) that is frequently amplified in breast and ovarian carcinomas
-EGF growth factor binds to ErbB receptor, activates ras/raf, activates MEK, MEK activates ERK, ERK goes into nucleus and phosphorylates Elk1 -fos=TF encoded by a proto-oncogene that is induced in response to GF and RTK stimulation -cancer treatment for mutations in ErbB: Herceptin (works on erbB-2 oncogene, breast cancer); Gefitinib (lung cancers); Erbitux (colorectal); |
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Tel/PDGFR oncogene activation
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-normal PDGF binds to its receptor and activates it
-Tel/PDGFR oncogene protein encodes a constituitvely active RTK so PDGF ligand is not required for signal activation= continuous proliferation signal |
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Gefitinib (drug)
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-used for cancer treatment targeted against oncogenes that drive tumor growth
-is a small molecule inhibitor of EGF (ErbB) receptor -sucess in activity against lung cancers that have point mutations in the EGF receptor (Herceptin and Erbitux also target erB oncogenes) |
