Fig. 3
BMI-associated net down-regulation of the two main signal transduction axes propagating and amplifying the initial insulin signal. Ligand-activated insulin receptor mediates activating tyrosine phosphorylation of IRS (insulin receptor substrate) proteins. Downstream of IRS, there are two major signal transduction branches: The PI(3)K → PDPK1 → AKT (right) and the SOS1::GRB2 → RAS → RAF → AP2K1 (MEK family) → MAPK3/MAPK1 (ERK family) kinase cascades (left). Tyrosine-phosphorylated IRS proteins bind PI(3)K and the SOS1::GRB2 complex. The activated SOS1::GRB2 complex promotes GDP-GTP exchange on p21ras (RAS), thereby activating the RAS → RAF → MAP2K1 (MEK family) → MAPK3/MAPK1 (ERK family) branch. Activation of PI(3)K (phosphatidylinositol-4, 5-bisphosphate 3–kinase) by IRS causes the production of PI3,4P2 (phosphatidylinositol-3, 4-bisphosphate) and PI3,4,5P3 (phosphatidylinositol-3, 4,5-triphosphate) which recruit PDPK1 (3-phosphoinositide-dependent protein kinase 1) and AKT proteins to the membrane. Subsequently, AKT is activated by PDPK1-mediated tyrosine phosphorylation. Finally, AKT and the ERK family kinases phosphorylate numerous cellular substrate proteins, resulting in their activation or inactivation (for details see Additional file 1: Supplementary Materials S1). Green and red coloring indicates signal transduction modules with corresponding mRNA levels that are negatively and positively correlated, respectively, with BMI in the present study