LYP's implications cause both increased or decreased susceptibility towards autoimmune and acquired diseases (LB96)

Abstract

When functioning properly, the immune system protects the body from foreign invaders with the help of T‐cells. An error in the formation of T‐cells in the thymus can lead to autoimmune diseases in which the T‐cells attack normal body tissues. When a T‐cell binds to an antigen, a signal transduction pathway is activated, forming a multimeric signaling complex known as the TCR signalosome. LCK, part of the signalosome, is a lymphocyte‐specific protein tyrosine kinase that phosphorylates a variety of proteins in order to activate the T‐cell receptor pathway. TCR stimulation also leads to the activation of LYP, a lymphoid tyrosine phosphatase that down regulates TCR signaling by removing phosphates from the signaling intermediates of the TCR signalosome. LYP also dephosphorylates Y394 of LCK, thus inactivating the kinase and inhibiting TCR signaling. The LYP R620W mutation prevents LYP from binding to the signalosome, resulting in a gain‐of‐function, leading to increased inhibition of TCR signaling. The LYP R620W mutation has been linked to a wide spectrum of human diseases, including a decreased risk in Crohn’s disease and increased risk to rheumatoid arthritis, and possible links to non‐autoimmune disorders such as cardiovascular disease. The Marshfield SMART (Students Modeling A Research Topic) Team modeled the mutated protein LYP R620W using 3D technology. Grant Funding Source: Supported by grants from NIH‐CTSA and NIH‐SEPA.