Cell Comm 2 - Dr White Flashcards
What is the major difference of “G alpha q” and “G alpha o” compared to other G proteins?
once GCPR attaches to this they associate with Phospholipase C not Adenyly Cyclase
How do IP3, DAG, Ca2+ associate with one another?
Phospholipase C cleaves membrane protein in PIP 2
- PIP2 procudes IP3 and DAG (2nd messengers)
- IP# triggers release of Ca2+ from ER via binding to an IP#-gated Ca2+ channel + triggers opening
- Ca2+ reeased into cytosol
- Ca2+ (Also 2nd messenger)
- CA2+ and DAG bind to protein kinase c (PKC)
- Conformational change in PKC = activation
- PKC phopshorylates a variety of membrane and subrstrates
What is calciums other function as a 2nd messenger
Binds to Calmoduin
Calmodulin binds to other proteins to activate their functions
What are the receptors , G proteins, Targets, 2nd messenagers, and effectors all relating to signal transduction via G proteins
Receptors: specific
G proteins: Gas, Gai, Gao, Gaq, Golf
Targets: adenylyl cyclase, phospholipase C
2 nd messengers: cAMP, DAG, IP3, Ca2+
Downstream effectors: PKA, PKC, gatedion channels
What are the other 3 types of singal transduction?
Tyosine Kinases
Jak Stat Receptors
Serine/threomime kinases
What are receptor Tyrosine Kinases?
- Signal transduction
- Enzyme linked receptors and enzymatic domain is in cytoplasmic tail of integral embrane protein
- RTK is used for response to growth factors to mediate growth factor signals
- cells with RTK are in contact indirectly with blood so add back serum factors and result is growth! (no serum = no growth)
- Cytoplasmic domain transmits signal through tyrosine kinase domain
- adds phosphate to tyrosine on proteins
What are the growth factors?
EGF = epidermal growth factos
PDGF - platlet dervived growth factor
NGF - nerve growth factor
FGF fibroblast growth factor
IGF-1 insulin like growth factor 1
all cause cells to grow and proliferate in cell culture and growth factors based on where its discovered but found in lots of cells
What is the function of RTK?
Binds to growth factor through extracellular domain
Signal through cytoplasmic domains (contains tyrosine kinas)
Phosporylates protein on tyrosine AA residues for activation
What are the steps of signal transduction through Receptro Tyrosine Kinase?
- Ligand binds to RTK
- Dimerization of 2 receptor monomers
- Autophosphorylation
- Receptor associates/binds to proteins w. the SH2 Domain (GRB2 in this case)
- The SH3 domain in GRB2 binds to SOS “son of sevenless”
- SOS binds to RAS
- RAS binds to RAF
- Map is initiated
- leads to changes in protein activaty or gene expression
What is SOS protein?
Son of sevenless
GEF and adds GTP to Ras
Name comes from R7 not being a gene that causes death when knoced out
What are the Steps of the Map Kinase Cascade?
- ras initates MAP kinase cascade
* “Mitogen activated protein Kinase” = cell proliferation - MAP kinase Kinase Kinase “RAF”
- MAP kinase Kinase “Mek”
- Map Kinase “Erk”
- Nucleus
- Increased gene transcription
- (no regulation leads to cancer)
SUMMARY SLIDE BOISSSSS
- Growth factor binds to receptor
- Receptor becomes active tyrosine kinase
- Autophosphorylates
- Binds to Grb2 – SOS – Ras – Raf – gene transcription through MAP kinase pathway
- Many signaling molecules are protooncogenes that can mutate into oncogenes and cause cancer
What are the steps for Jak - STAT receptors?
More direct route for impacting transcription
Erythropoeitin EMplys jak STAT to initiate signaling
- Ligand binds to receptors - dimerie - then binds JAKS (janus Kinases)
- JAKs phosphorylate each other
JAKs phosphorlate receptors - Receptor binds and phosphorylates STATs (signal transducer and Activators of Transcription Proteins )
- STATs separate from receptors, dimerize and enter nucleus - binds to DNA and causes transcription of terget genes
What is the Serine Threonine Receptor and Smad
ANother more direct route: R-smad = receptor specfific Smad and forms complex with Co-Smad: Common Smad
Activated receptor by (phosphorlaytion) binds to R-Smad (receptor specific) and Phosphorlates R-Smad
R-Smad binds to Co-Smad (common Smad) and moves into Nucleus to impact transcription of target genes
EX: HEPCIDIN (IRON metabolism)
What is hereditary hemachromatosis
uncontrollable iron absorption
iron overloading
toxic levels of iron get depositied in organs
What aids in transport of iron into Enterocytes? (intestinal cells)
DMT1 - Iron into intestinal cell
Ferroportin - iron out of intestinal cell and into blood
Hepcidin a protein made in the liver regualtes iron homeostasis
How does Hepcidin work?
Hepcidin exerts its regulatory effect by binding to ferroportin
Ferroportin is receptor for hepcidin
Hepcidin binds to ferroportin which causes internalization of ferroportin which is destroyed by proteolysis
high [Fe] - hepcidin expression is up and ferroportin levels are down
low [Fe] - hepcidin expression is down and ferroportin is up
What is the cause of hereditary hemochromatosis ?
Genetic Iron overloading
- Autosomal ressive
- (most common autosomal recessive dieasse genes in man)
- mutations in HFE gene ( hereditary iron)
- Cys 282 to Tyr (C282Y)
- HFE protein membrane bound that associates with TfR2 and expresses Hepcidin
- Found in Liver
- HFE binds to transferrin receptor (TfR)
What Pathway does Hfe work through?
Its works through smad pathway to induce hepcidin expression
If Hfe is mutated it cannot assocate with TfR2 (trans-ferrin Receptor 2) which means no hepcidin expression thus causing iron overloading
