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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.
peptide hormone, synthesized in adipose, involved in insulin resistance
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)?
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)?
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?
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?
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
target of rapamycin, phosphphorylates ser residues on IRS-1 (inhibiting its tyr phosphorylation)
What is an example of downstream feedback inhibitory mechanism?
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)
Reduce blood glucose and prevents FFA-induced muscle insulin resistance by inhibiting the Iκκβ pathway
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
(rosiglitazone) - insulin-sensitizing drugs that activate the transcription factor PPAR-Ï’ which in turn increase transcription of CAPs, also may affect circulating lipid profile

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