Receptor Mechanism III
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Name 4 examples of enzyme linked receptors
Tyrosine receptors kinase JAK/STAT Serine threonine receptor kinase
Name 3 features of enzyme-linked receptors
Predominantly single transmembrane domain receptors Activation leads to activation of receptor kinases Activation leads to the activation of multiple signalling pathways
What processes are enzyme-linked receptors involved in
Cell growth Division Differentiation Survival Migration
What happens when an agonist binds to a kinase receptor
Dimerisation of agonist and phosphorylation of specific residues (e.g. tyrosine)
What does Grb-2 bind to and what happens
Tyrosine through SH2 domains, then interacts and binds with GEF (guanine-nucleotide exchange factor) through SH3 domains. GEF activates RAS with GDP.
What happens when RAS is activated
GDP is expelled and exchanged for GTP, to form Ras-GTP -> more intracellular pathways.
describe activation of PI 3-kinase
Phosphorylates PIP2 to PIP3 -> Binds to PDK1 and PKB PDK1 phosphorylates PKB and activates PKB so it dissociates
Describe insulin receptor vs tyrosine kinase receptor
Alpha chain Disulphide links Beta chain
Describe insulin receptor action
Conformational change, beta subunits brought together for phosphorylation, recruiting IRS through SH2 domain.
What does IRS do
IRS recruits activated PI 3-kinase, (and Ras, phospholipase C) phosphorylated to PIP3 then PDK1 then PKB, dissociation to active PKB. Glycogen synthesis, protein synthesis
What do kinases do vs what do phosphatases do
Kinases add phosphates Phosphatases remove phosphates
Describe the activation of phosphatases
Activation of receptors leads to phosphorylation, de-phosphorylation leads to inactivation Phosphatases are activated. The signalling procvess sets in motion events that lead to signal termination
Inactivation of Ras
GDP replaced by GTP to form active complex with Raf.
What does active Ras do
Interacts with GTPase activating protein (GAP), stimulating GTPase activation. GTP dissociates, Ras deactivated to inactive form.
Describe some harmful mutations in key regulatory mechanisms
Loss of phosphatase activity - Increased phosphates Receptor expression - Increases Loss of GTPase activity - Increased Ras activity Loss of phosphatases - Inhibiting inactivation proces
Describe some harmful mutations in key regulatory mechanisms
Loss of phosphatase activity - Increased phosphates Receptor expression - Increases Loss of GTPase activity - Increased Ras activity Loss of phosphatases - Inhibiting inactivation process
What happens when a ligand growth hormone binds to a JAK-stat receptor
Dimerisation, phosphorylation of JAK proteins. Receptor itself is phosphorylated. Receptor acts as docking site for STAT. Dimer formed. Dimer dissociates and migrates to nucleus, stimulating/regulating gene expression at target gene.
Describe serine-threonine kinase receptor. (E.g. TGF-Beta)
Requires type 1 and type 2 receptors, where both have serine/threonine kinase domain. TGF-beta molecule binds to type II receptor, leading to conformational change, dimerisation with type 1 receptor. Type 2 receptor phosphorylates type 1 receptor, leading to recruitment of Smad2 and Smad3. Phosphorylation of Smad. Smad dimerises with Smad4, and dissociates. The dimer moves to the nucleus, where it regulates gene expression.
What are intracellular receptors activated by
Molecules that readily pass across the plasma membrane, and are largely insoluble in aqueous environments e.g. thyroid hormones.
Describe steroid receptor mechanism (e.g. cortisol)
Cytosolic receptor - Bound to heatshock protein (HSP). Cortisol binds to HSP+GR protein (glucocorticoid receptor) causing dissociation of HSP. GR with glucocorticoid forms dimer. Dimer moves into nucleus where it binds to a glucocorticoid response element, leading to transcription increase.
Describe thyroid hormone receptor mechanism
T3 (Thyroid hormone) bound to binding globulin, diffuses into nucleus. Binds to thyroid hormone receptor. Activates other associated proteins to form thyroid response element, to lead to transcription.