Activation of the RTK

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• Activation of Insulin Receptor (RTK)

• Step 1: Ligand (insulin) binds to RTK 

• Step 2: Two kinase domains of Beta subunits brought together, auto- crossphosphorylating the tyrosines (Y) of the Beta subunits

• Step 4: SH2 domain of adj. Insulin Receptor Substrates (IRS-1) now recognizes Pleckstrin domain of PIP2

• Step 4a: IRS-1 is now phosphorylated an additional three times by RTK, while previous phosphates are removed to conserve Energy

•  RTK = 2 outside alpha subunit + 2 cytosolic Beta subunits + 1 transmembrane helix domain + extracellular ligand-binding domain

• Step 4b: Phosphoinositide 3-kinase (PI 3-K) recognizes phosphotyrosine of IRS-1 and binds to become phosphorylated

• Step 5b: PIP2 phosphorylated to become PIP3 by PI 3-K

• Step 6b: PIP 3 recruits PDK-1 to membr, activating kinase activity

• PDK-1 activity is similar to adenyl cyclase b/c both are brought to the membrane

• Step 7: PDK-1 activates non membrane bound AKT protein (a kinase)

• Step 8: AKT activated via Pi by hydrolysis of ATP

• Step 9: AKT activates glycogen synthesis and glucose uptake through crazy phosphorylation!!!

• Step 3: IRS-1 also separately phosphorylated by RTK

• Step 10: Glut4 receptors are transported to the cell membrane