Exam 4 - IR/PI-3K/Cytokine Receptor Flashcards
What type of receptor is IR?
IR (insulin receptor) is a RTK (receptor tyrosine kinase)
What is normal (fasting) blood glucose level? What maintains this?
Normal (fasting) blood glucose levels in humans are maintained at ~5.5 mM by the opposing actions of insulin and glucagon
What happens to blood glucose after a meal?
↑ blood glucose after a meal results in:
↑ secretion of insulin from pancreatic β cells
What does insulin do to blood glucose levels?
↓ blood glucose levels by promoting glucose uptake in muscle and adipose tissue and glucose storage in liver
What happens to excess sugar in the body?
Excess sugar causes insulin release, which causes glucose uptake by tissues and its subsequent storage as fat or glycogen.
Insulin is anabolic or catabolic?
Insulin is anabolic = signals the building of macromolecules, cells, and tissues
↑ Insulin affects which cellular process we have to know?
↑ glucose uptake ↑ amino acid uptake ↑ acetyl CoA → fatty acids ↑ glucose → glycogen ↑ protein synthesis ↓ pyruvate → glucose (↓ gluconeogenesis)
Describe the structure of IR
Insulin receptor (IR) monomer is comprised of an external α-subunit linked by disulfide bonds to the internal β-subunit. Two of these monomers are linked together by disulfide bonds so that IR is already functionally ‘dimeric’ without insulin. When insulin binds, it causes a conformational change in the β– subunits that activates their kinase activity and brings the cytoplasmic domains closer together so they can phosphorylate each other. Thus, the two β–subunits trans- phosphorylate each other, just as occurs with other RTKs.
Insulin receptor is an RTK, so it uses adapter proteins like ___________.
IRS (insulin receptor substrate)
IRS
IRS (insulin receptor substrate) is an adaptor protein, although it is more commonly called a docking protein that is recruited by its PTB domain to the phosphotyrosines on IR. IRS itself becomes phosphorylated on many tyrosines by the actions of IR. These P-Tyr serve as recognition sites for other signaling proteins as described for other RTKs
What type of domain does IRS have?
PTB
The docking protein IRS interacts with what other proteins?
Grb2/SOS (Ras-GEF)
PLCγ
PI3-kinase
IRS to Grb2
- Adapter protein: SH2 domain of RTK/docking protein to SH3 domains of Ras-GEF (aka SOS)
- Ras-GEF (SOS) exchanges GDP for GTP in Ras and activates it
- Ras phosphorylates Raf, which phosphorylates MEK, which phosphorylates MAPK
- MAPK leads to cell proliferation, gene transcription
IRS to PLCγ
Activates inositol phospholipid signaling pathway (diacylglycerol & IP3 allow docking and activation of PKC) leading to cell proliferation and gene transcription
IRS to PI3-kinase
Leads to Akt kinase (PKC), then TOR kinase
Leads to: protein translocation, glucose transporter, protein synthesis, cell growth)