Insulin Signaling
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- What kind of phosphorylation sites do IRS proteins have?
- tyr, ser, thr
- Is F2,6BP an autoregulator of glycolysis?
- No, because it is not an intermediate in the process of glycolysis.
- What kind of an effect would inhibiting tyr Pase on an IRS protein have?
- Stimulate insulin signaling cascade
- In what tissues is GLUT4 expressed? Where is it stored in the cell?
- Muscle, adipose, brain, etc., but not pancreas. It is stored in vesicles.
- What brings GLUT4 to the cell surface?
- insulin binding to its receptor
- What is leptin?
- peptide hormone, synthesized in adipose, it binds to brain cells and controls appetite.
- Adiponectin
- peptide hormone, synthesized in adipose, involved in insulin resistance
- resistin
- peptide hormone, synthesized in adipose, involved in insulin resistance
- What tissue has the highest glucose intake?
- skeletal muscle
- Will there be high, normal, or low amounts of glucose in the blood if muscle insulin receptors are knocked out (after treatment with glucose)?
- normal
- Will there be high, normal, or low amounts of glucose in the blood if adipose insulin-dependent glucose transporters are knocked out (after treatment with glucose)?
- high
- Insulin binds to what subunit of the insulin receptor?
- the α subunits
- What happens to the β subunit upon insulin binding?
- The α subunits activate the β subunits, which then autophophosylate each other and activate their tyr kinase activity
- When is the insulin receptor tyr kinase active?
- when insulin is bound to the α subunits and the β subunits become autophosphorylated
- What functions does the SH2 class of proteins have?
- kinase, phophorylase, G-protein activators
- What are 4 targets of the insulin receptor tyr kinase?
- IRS proteins, SHC proteins, Cbl Activated Proteins, and Gab proteins
- By what means do different tissue types respond differently to insulin binding?
- by expressing a variety of insulin receptor target proteins
- What are caveolae?
- structural components (subdomains) of the plasma membrane used in the CAP pathway, aka lipid rafts
- The MAP kinase cascade controls what cellular function?
- cell growth
- What insulin-dependent pathways can activate the MAPK pathway?
- IRS-2, Shc proteins, Gab proteins
- What proteins "dock" at phosphorylated IRS proteins?
- SH2 proteins
- IRS-1 controls what cellular activity?
- mitogenic
- Where is phosphatidyinositol-4,5-bisphosphate found?
- the cell membrane
- IRS-2 controls what cellular activity?
- carbohydrate metabolism, glucose transport
- Gab-1 controls what cellular activity?
- initiates the MAPK pathway
- What are PDK1s? By what are they activated?
- phosphatidyl dependent kinase-1s, they're activated by 3-phosphorylated PIP2 (phosphorylated by PI3K)
- What does the activation of Cbl-CAP do?
- translocates GLUT4 to the cell membrane
- What are the downstream functions of the PI3K pathway?
- increase glycogen synthesis, GLUT4 translocation to the cell membrane, and cell growth
- When does phosphatidyinositol-4,5-bisphosphate become an active intramembranous signaling molecule?
- When it is phosphorylated at C3 by PI3K
- What are the products of phospholipase C cleavage of phosphatidyinositol-4,5-bisphosphate?
- inositol-1,4,5-triphosphate and diacyl glycerol (both are signaling molecules)
- Is the GLUT4 translocation via the CAP pathway PI3K-dependent or -independent?
- PI3K-independent
- Free fatty acids and TNF-α activate what? What does this do to IRS proteins?
- ser/thr kinases, downregulates them by inhibiting IRS tyr phosphorylation and leads to insulin resistance
- What is the purpose of ser and thr phosphorylation sites on IRS proteins?
- To modulate the activity of the tyr phosphorylation site
- What kind of effect would blocking IRS Pase activity have on the insulin-mediated signal?
- Propagate the signal
- What is required of the IRS proteins for SH2 to "dock?"
- phosphorylation of tyr sites
- mTOR
- target of rapamycin, phosphphorylates ser residues on IRS-1 (inhibiting its tyr phosphorylation)
- What is an example of downstream feedback inhibitory mechanism?
- mTOR
- How does active PKCζ regulate IRS activity?
- PKCζ phosphorylates the IRS protein and dissociates it from the insulin receptor, inhibiting it
- What molecules activate PKCζ?
- TNFα, Iκκβ
- How does JNK inhibit IRS activity?
- By phosphorylating a ser residue on IRS, inhibiting its tyr phosphorylation by the insulin receptor
- PTPases do what?
- dephosphorylates tyr residues on IRS
- Are PTPase knockouts more or less sensitive to insulin?
- more (less tyr phosphorylation = more IRS activity)
- Salicylates
- Reduce blood glucose and prevents FFA-induced muscle insulin resistance by inhibiting the Iκκβ pathway
- SHIP2
- dephosphorylates C3 of PI3P, stopping signal propagation
- Explain genetic induction of insulin resistance.
- IR or other downstream proteins may be defective, reducing the effective signal induced by insulin
- thiazoladinediones
- (rosiglitazone) - insulin-sensitizing drugs that activate the transcription factor PPAR-Ï’ which in turn increase transcription of CAPs, also may affect circulating lipid profile