Signal Receptors

Nikhil Dhall
Mind Map by Nikhil Dhall, updated more than 1 year ago
Nikhil Dhall
Created by Nikhil Dhall over 5 years ago


Brief overview of some intracellular signaling pathways leading to apoptosis and cell proliferation

Resource summary

Signal Receptors
1 GPCR: 7 membrane spanning alpha helixes with ligand binding site
1.1 Cytosolic surface
1.1.1 Trimeric G protein: Galpha, Gbetagamma. Held to PM by lipid anchors Galpha: GTP binding activated by GCPR GEF activity which exchanges GDP for GTP Activate Adenylyl Cyclase to make cAMP (2nd messenger) cAMP binds and removes 2 regulatory subunits from PKA thereby activating PKA Skeletal muscle: glycogen phosphorylase --> breakdown of glycogen ATP used for muscle contraction Transported to nucleus to regulate transcription by activating CREB (slower effect) Makes mRNA and proteins (longer lifetime and effect) cAMP Structure: ATP loses ppi and adenylyl cyclase catalyzes bond from 5' p to 3'OH. cAMP phosphodiesterase breaks 3' to make AMP (lose effect). Causes finite lifetime of signal Bound to Palmitoyl (anchor) G-a has intrinsic GTPase that cleaves GTP to limit activating effect Cholera toxin inhibits GTPase on Ga so it is continuously active Continuous activation of cAMP cAMP opens the CFTR (cystic fibrosis) Cl- channel which is an active transporter that PUMPS OUT Cl - (using ATP) into the intestinal lumen As Cl- and other ions leave the cell, water leaves the cell into the lumen to balance the osmolarity (concentration of solute difference) leading to diarrhea Cholera toxin is an AB toxin B subunit binds to GMI glycolipid and is activated by A subunit (proteolysis) to enter the cell - A1 is the toxin made of NAD+ that ADP ribosylates the G-a GaI = A2 GPCR - inhibit adenylyl cyclase Gas = B - activate adenylyl cyclase Gaq=A1 - Activate PLC GBY & Galpha Q activates PLC (Muscarinic GPCR acetylcholine receptors in cardiac cells), Gbg activates K+ channels until Galpha phosphorylates GTP --> inactivation K+ flows out of cell rapidly --> low [K+] intracellular --> slows contraction rate of heart Activated phopholipase C (PLC) PLC targets Phosphoinositol Phospholipid (PIPL = PI45bp) inositol triphosphate (IP3) Open Ca++ channel in ER --> HIGH [CYTOSOLIC Ca++] Calmodulin (CaM) binds to Ca++ CaM binds CaM-Kinase (increase effect of Ca++) Diacylglycerol (DAG) Activate Protein Kinase C (PKC) if high Ca++ GaQ Bound to GPI (anchor)
1.2 Extracellular space: ligand binding site
1.2.1 Skeletal muscle: Adrenaline binds to GPCR
1.3 Rhodopsin is another type of GPCR where photons are
1.3.1 G-Protein is transducin Alpha activates cGMP phosphodiesterase Hydrolyzes cGMP --> GMP GMP Shuts Cation channel Nerve signal for light
2.1 enzyme couple receptor class. Structure: 1 alpha helix that crosses PM.
2.1.1 step 1: signal reception leads to dimerization of monomers that activates enzymatic function of RTK = tyrosine kinase (phosphorylate tyrosine)
2.1.2 Variation: direct association with an enzyme step 1: dimerization of 2 nonidentical receptors by extracellular signal binding step 2: association and activation of cytoplasmic enzyme --> signal transmission via enzyme activity.
2.2 First target of RTK = dimer binding partner
2.2.1 Autophosphorylation of dimer on several tyrosine residues enzymes or adaptor proteins bind to phosphorylated tyrosines on RTK Autophosphorylation to make pY modifies dimer binding partner activate enzymatic activity or make 2nd messenger RAS - monomeric G protein (gtp-ase) anchored to cytoplasmic PM that is activated by RTK and activates other proteins PIPL used in GPCR triggered phospholipase C pathway PI3 kinase is activated by RTK Converts IP2 to IP3 (PIPL) PIPL docks AKT (ser/thr protein kinase) Protein kinase 1 attaches to PIPL in PM and phosphorylates to AKT Partial activation of AKT Protein Kinase 2 in cytosol and phosphorylatees AKT Full activation of AKT Activated AKT phosphorylates protein BAD and releases BCL2 from BAD BAD - when unphosphorylated is a signal for apoptosis. Activation of BAD is REMOVAL OF ACTIVITY BACL active when not bound to BAD (when BAD is phosphorylated) and signals for cell growth Activates TOR "target of Rapamycin= anticancer drug" (ser/thr kinase) TOR inactivates a TOR inhibitor reduces protein degredation Promotes protein synthesis NOTE: when tor is active, it promotes growth, and destroyed inhibitor which would cause protein loss PI3K have SH2 domains activated by pY on RTK Phosphorylation of PI 4,5 bp to PIP3 PIP3 is recognized by PH (pleckstrin homology) which activates PKB PKB stimulates GLUT4 translocation to the PM, as well as activates glycogen synthase RTK pY binds SH2 domain of Grb2 which then activates SOS (a RAS GEF) SOS exchanges RAS GDP for GTP --> activation of RAS RAS GTP activates RAF(MAPKKK) MAPKK kinase phophorylates MANY MAPK kinase (MEK) MAPK Kinase (MEK) phosphorylates MANY MAP kinase (ERK) activates many MAP - Mitogen Activating Proteins (specific kinases and transcription regulators) to go through the cell cycle Cell proliferation RAS - monomeric G protein (gtp-ase) anchored to cytoplasmic PM that is activated by RTK and activates other proteins Insulin binds Insulin receptor activating IRS-1 which binds GRB2 also to activate SOS IRS-1 also activates PI3-K by binding to SH2 domain
2.2.2 Dimer (bound transiently depending on affinity noncovalently) lasts as long as signal is bound
3 Others
3.1 Jak-Stat
3.1.1 Dimer receptor activated upon binding of cytokine Activation of receptor activates JAK - an extrinsic kinase "Janu's Kinase" Jak phosphorylates the receptor Jak phosphorylates STAT - a protein with an NLS that will go to nucleus to control gene transcription Function as immunomodulator or regulator of cell growth and differentiation; can induce differentiation and inflammation (paracrine) or fever (endocrine)
3.2 Ser/Thr Receptor
3.2.1 binding of ligand activates intrinsic kinase Autophosphorylation of receptor Phosphorylation of SMAD - a TF for gene regulation
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