Absence of IQGAP1 Protein Leads to Insulin Resistance

Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK/ERK pathways. IQGAP1 is a scaffold protein that interacts with multiple binding partners and integrates diverse signaling cascades. Here we show that IQGAP1 associates with both IR and IRS-1 and influences insulin action. In vitro analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine-binding domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. Consistent with these observations, both IR and IRS-1 co-immunoprecipitated with IQGAP1 from cells. Investigation of the functional effects of the interactions revealed that in the absence of IQGAP1, insulin-stimulated phosphorylation of Akt and ERK, as well as the association of phosphatidylinositol 3-kinase with IRS-1, were significantly decreased. Importantly, loss of IQGAP1 results in impaired insulin signaling and glucose homeostasis in vivo. Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling.

Engulfment adaptor phosphotyrosine-binding-domain-containing 1 (GULP1) is a nucleocytoplasmic shuttling protein and is transactivationally active together with low-density lipoprotein receptor-related protein 1 (LRP1)

APP (amyloid precursor protein) and LRP1 (low-density lipoprotein receptor-related protein 1) have been implicated in the pathogenesis of AD (Alzheimer's disease). They are functionally linked by Fe65, a PTB (phosphotyrosine-binding)-domain-containing adaptor protein that binds to intracellular NPxY-motifs of APP and LRP1, thereby influencing expression levels, cellular trafficking and processing. Additionally, Fe65 has been reported to mediate nuclear signalling in combination with intracellular domains of APP and LRP1. We have previously identified another adaptor protein, GULP1 (engulfment adaptor PTB-domain-containing 1). In the present study we characterize and compare nuclear trafficking and transactivation of GULP1 and Fe65 together with APP and LRP1 and report differential nuclear trafficking of adaptors when APP or LRP1 are co-expressed. The observed effects were additionally supported by a reporter-plasmid-based transactivation assay. The results from the present study indicate that Fe65 might have signalling properties together with APP and LRP1, whereas GULP1 only mediates LRP1 transactivation.