Human disease and gain-of-function mutations in the KIT/KITL signaling pathway

Abstract

KIT ligand (KITL) interacts with and activates the class III receptor tyrosine kinase KIT. In vertebrates, the KIT/KITL signaling pathway is involved in the development and proliferation of germ cells, melanocytes, hematopoietic cells (mast cells and erythrocytes), and interstitial cells of the Cajal in the gastrointestinal tract. These cells express KIT on their surface and consequently respond to KITL expressed from surrounding supporting cells. Upon binding, KIT dimerizes and a reaction cascade is initiated within the cell expressing KIT. Abnormal activation of the KIT/KITL signaling pathway has been associated with several human neoplastic diseases, such as gastrointestinal stromal tumors (GISTs), systemic mastocytosis, acute myeloid leukemia, sinonasal natural killer/T-cell lymphoma, and testicular seminoma. GISTs, which are mesenchymal neoplasms in the GI tract, are the most extensively studied diseases with regards to constitutive activation of the KIT/KITL pathway. The most commonly used pharmacological intervention for treating neoplastic disorders related to the misregulation of this pathway is a small-molecule inhibitor of KIT known as Gleevec. However, this treatment is not effective against all activating mutations in KIT. Other therapeutic drugs are currently being tested and designed to target abnormal KIT expression associated with gain-of-function (GOF) mutations. The KIT/KITL pathway and the role of KIT in disease must be examined further so that more effective treatments can be designed.