tyrosine residue
Depending on which ____________ gets phosphorylated, a RTK can have different downstream signalling effects.
Ligand binding initiates receptor dimerization
• Phosphorylate the adjacent receptor (tyrosine residues)
• Signaling molecules are recruited
What 3 things are happening here?
Recognize phosphate group at receptor
Recognize phosphate group at lipid membrane
Recruits accessory proteins; does not bind to phosphate
What is the Role of SH2 and PTB?
What is the role of PH?
What is the role of SH3?
Receptor Tyrosine Kinase (RTK)
Activate Ras; when it binds to GTP
Insulin!!!!!
What is this? What is one important thing it can do?
What it an IMPORTANT example of this?
Serine/Threonine kinase domains activate SMAD
Travels to nucleus and activates transcription
1) Binding of the ligand induces
dimerization.
2) Serine/threonine are
phosphorylated
3) Activation of SMAD
by phosphorylation
4) SMAD oligomerize
and regulate gene expression.
What is going on here?
What does SMAD do?
MAP-Kinase Cascade (mitogen-activated protein kinase)
Active Ras
What is this called?
What causes a MAP cascade?
INACTIVATES Ras; Activates Ras GTPase activity, causing GTP to be hydrolyzed; Ras-GAP keeps most of the Ras inactive
GEF ACTIVATES Ras; Causes Ras to eject GDP, so that it can binds free GTP
Inability to hydrolyze GTP, thus it would be constitutively active! Increasing cell proliferation
What does Ras-GAP do?
What does Ras-GEF do?
What would a mutation of Ras lead to?
Soluble Guanylyl cyclase
Rapid smooth muscle cell RELAXATION
Nitroglycerides
cGMP phosphodiesterase-V (PDE-V) that inactivates cGMP
What does NO activate?
What is the effect?
What is a medication that increases NO?
What does Viagra work on?
Tyrosine Kinase Receptor
Insulin bind to α subunit
Causes β subunits to autophosphorylate
The Activated ITRK then acts on targets such as Insulin Receptor Substrate-1 (IRS-1)
What type of receptor is the insulin receptor?
Insulin binds to ______? Causes what to happen?
Phospholipase C (PLC) activates protein phosphatases; REGULATES Lipid and Glycogen Synthesis
PI-3 kinase; Insertion of GLUT4 receptors
MAPK; modulates Gluconeogenesis and glycogenolysis via gene expression
What are the three insulin pathways?
PI-3-K in the LIVER
FKHR → Gluconeogenesis ↓
GSK3 → Glycogen Synthesis ↑
mTOR → Protein Synthesis ↑
JNK (SREBP, PGC) → Lipid Lipoprotein homeostasis and lipogenesis ↑
Which pathway is this and where does it happen?
What does each orange oval effect?
Insulin inhibits the expression of PEPCK, the RATE-LIMITING step of gluconeogenesis
Glucagon
Ras/MAPK pathway
Prevents AF2 from binding and activating PEPCK gene
Insulin inhibits the expression of the gene for what protein?
It is opposed by which signaling factor?
Which pathway mediates this effect of insulin?
What does IREB do?
PEPCK↓ → Gluconeogenesis inhibited
GAPDH↑ Glycolysis is stimulated
Insulin has these effects on these enzymes. What is the result?
Insulin Responsive Element (Transcription factor)
PEPCK Gluconeogenesis
GAPDH (GA-3-PDH) Glycolysis
What is an IRE?
What two important genes are modified by IREs?
Protein Kinase A
Fructose 2,6 bisphosphatase
Shuts off gluconeogenesis
Glucagon
What two things does insulin cause to be dephosphorylated? What effect does this have?
What signaling factor opposes insulin here?
Stimulating Glycogen Synthase (B)
Inhibiting Glycogen Phosphorylase (A)
What two Enzymes is Insulin acting upon (A and B)?