Insulin receptor tyrosine kinase autophosphorylates upon insulin binding. The primary immediate downstream substrate of activated insulin receptor kinase that initiates the PI3K-Akt pathway is:

• A GRB2
• B Phospholipase C-gamma
• C STAT5
• D IRS-1 (Insulin Receptor Substrate-1) ✓

Explanation

Upon insulin binding, the insulin receptor undergoes trans-autophosphorylation of tyrosine residues in the intracellular kinase domain. The activated receptor then phosphorylates IRS-1 (and IRS-2) on multiple tyrosine residues. Phospho-IRS-1 serves as a docking platform for the p85 regulatory subunit of PI3-kinase, activating PI3K which generates PIP3, leading to PDK1 activation and Akt (PKB) phosphorylation. GRB2 is engaged via IRS-1/Shc and activates the MAPK/RAS pathway (proliferative signalling). PLC-gamma and STAT5 are not primary insulin receptor substrates.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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