![]() ![]() ![]() IRS proteins are directly phosphorylated by InsR on tyrosine residues located in multiple YxxM motifs, which are evolutionarily conserved in all IRS paralogs (IRS1-4). Insulin receptor substrates (IRS proteins) are conserved mediators of insulin tyrosine kinase receptor (InsR) action, intimately involved in the development of insulin resistance 1. Insulin resistance is a pathological state of insulin receptor pathway desensitization that usually precedes and eventually leads to type II diabetes. Insulin signaling has been studied extensively in the past decades, in an attempt to better understand the pathomechanism of diabetes, one of the greatest medical burdens in the developed world. Our findings not only show an unusual dependence of SHP2 catalytic activity on Ser/Thr phosphorylation sites in IRS1 and CD28, but also suggest a negative regulatory mechanism that may also apply to other tyrosine kinase pathways as well. What is more, the relatively stable pre-catalytic state of SHP2 could potentially be useful for inhibitor design. The structure of SHP2 has been determined with three different substrate peptides, unveiling the versatile and highly dynamic nature of substrate recruitment. Here we present a concise structural study on how the activity of SHP2 phosphatase is controlled by an asymmetric, dual phosphorylation of its substrates. While exploring the role of phosphoserines, we have detected a direct link between Tyr-flanking Ser/Thr phosphorylation sites and regulation of specific phosphotyrosine phosphatases. However, the molecular details of this process have mostly been elusive. Serine/threonine phosphorylation of insulin receptor substrate (IRS) proteins is well known to modulate insulin signaling.
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