From Phosphorylated IRS to GLUT4 at the Membrane | Visual AI Learning Guide

Start with phosphorylated IRS at the membrane. Its phosphotyrosine motifs recruit PI3K, which converts PIP2 into PIP3. PIP3 is the docking signal that pulls Akt to the membrane, but recruitment alone is not activation: Akt also needs phosphorylation by PDK1 and mTORC2. Only then does active Akt phosphorylate AS160. AS160 normally holds GLUT4 vesicles inside the cell by keeping Rab proteins inactive; phosphorylation switches that brake off, the vesicles travel to the surface, and GLUT4 inserts into the membrane. Watch the transporter count at the surface rise as the vesicles fuse, and note that this whole relay takes only minutes.

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Phosphorylated IRS proteins carry phosphotyrosine motifs that are recognized by the SH2 domain of the regulatory subunit of phosphoinositide 3-kinase (PI3K). This binding brings PI3K to the membrane and activates its catalytic subunit, which phosphorylates the membrane lipid PIP2 to PIP3. PIP3 acts as a docking site: Akt binds PIP3 through its pleckstrin homology domain and is recruited to the membrane. Recruitment alone is not enough. At the membrane, Akt is phosphorylated by PDK1 at Thr308 and by mTORC2 at Ser473; both phosphorylations are required for full activity. Active Akt then phosphorylates AS160 (also called TBC1D4), a Rab GTPase-activating protein. Unphosphorylated AS160 keeps Rab proteins in their inactive GDP-bound state, which holds GLUT4-containing vesicles inside the cell. When Akt phosphorylates AS160, its GAP activity is inhibited, Rab proteins become GTP-bound and active, and GLUT4 vesicles move along the cytoskeleton to the plasma membrane, where they dock and fuse. The result is an increase in GLUT4 molecules at the cell surface, which raises glucose uptake into muscle and adipose tissue. The whole sequence from receptor to transporter insertion takes minutes. In the absence of insulin, GLUT4 is recycled back into intracellular storage vesicles, and uptake falls again.