Question

If you knocked out (deleted) the SH2 domain of IRS-1, where would you expect to find most of the cellular ERK?

A. In the cytoplasm

B. evenly distributed between cytoplasm and nucleus

C. In the extracellular space

D. In the nucleus

E. Embedded in the plasma membrane

Answer 1

ANS A. In the cytoplasm

INSULIN GLUCOSE UPTAKE INSULIN RECEPTOR PLASMA MEMBRANE PLASMA | PIP2 → PIP3 CAP Cbl Crk GLUT4 translocation Sh2 АКТ Grb2 C3G p110 Dissociation TC10 SOS PAKT GTP P13-K RAFRAS GLUT4 Vesicle mTOR inactive PGSK3 MEK1 active elF2 PROTEIN SYNTHESIS Forkhead transcription factors ERK/MARK PATHWAY active Glycogen Synthase PROTEIN SYNTHESIS INHIBITION of GLUCONEOGENESIS GLYCOGEN SYNTHESIS

diagram of the insulin signaling pathway .

Binding of insulin to the α subunit induces a conformational change, allowing autophosphorylation of a number of tyrosine residues in the β subunit. In ERK branch of the pathway, growth factor binding protein 2 (Grb2) binds to the phosphotyrosine residues of the activated insulin receptor by its Src homology 2 (SH2) domain, which leads to the activation of downstream Ras, Raf, and the MEK1 kinase cascade, resulting in phosphorylation and activation of MAP kinase isoforms ERK1 and ERK2. In the Akt-signaling branch,

the insulin receptor β residues are recognized by phosphotyrosine-binding (PTB) domains of adaptor proteins, such as members of the insulin receptor substrate family (IRS), leading to the phosphorylation of key tyrosine residues on IRS proteins, some of which are recognized by the SH2 domain of the p85 regulatory subunit of PI 3-kinase (a lipid kinase).

The catalytic subunit of PI 3-kinase, p110, then phosphorylates phosphatidylinositol (4, 5)-bisphosphate (PIP2) leading to the formation of phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3). Akt activation re- quires protein kinase 3'-phosphoinositide-dependent protein kinase-1 (PDK1), which leads to the phosphorylation of Akt. Once active, Akt enters the cytoplasm, where it leads to the phosphorylation and inactivation of glycogen synthase kinase 3 (GSK3), which activates glycogen synthase.

PI3-kinase and Akt are known to play these important roles in GLUT4 translocation to the plasma membrane and, as a result, glucose enters the cell.