Class III and V receptor tyrosine kinases (Class III/V RTKs)

Class III and V receptor tyrosine kinases (RTKs) are two structurally related families of cell surface receptors characterized by an extracellular domain with immunoglobulin-like loops and an intracellular tyrosine kinase domain split by a kinase insert sequence [1][2]. Class III RTKs include Platelet-derived growth factor receptors (PDGFRα/β), KIT, CSF1R, and FLT3, which play vital roles in hematopoiesis and the development of mesenchymal tissues [1][5]. Class V RTKs consist of the Vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), which are the primary drivers of vasculogenesis, angiogenesis, and lymphangiogenesis [3]. Dysregulation of these receptors through mutations, gene amplifications, or autocrine signaling loops is a hallmark of several cancers, including gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), and renal cell carcinoma [4]. Because of their critical roles in tumor cell survival and the formation of tumor-associated blood vessels, these receptors are major targets for multi-kinase inhibitors [4]. Drugs such as sunitinib and sorafenib act by competing with ATP for binding to the intracellular kinase domain, thereby blocking downstream signaling pathways like MAPK/ERK and PI3K/AKT [4]. Therapeutic inhibition of these classes is often associated with specific side effects, such as hypertension and hand-foot skin reactions, due to their roles in normal vascular and skin homeostasis [4]. Sources: [1] Lemmon & Schlessinger, Cell 2010; [2] Hubbard, Prog Biophys Mol Biol 1999; [3] Shibuya, Biomolecules 2020; [4] Roskoski, Pharmacol Res 2019; [5] Verstraete & Savvides, Nat Rev Mol Cell Biol 2012.

Other names

Split-kinase domain receptor tyrosine kinasesType III and Type V RTKsPDGFR and VEGFR family receptors

ATP-competitive inhibition of the intracellular tyrosine kinase domain, preventing autophosphorylation and downstream signaling through the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways [1][4].