Receptor Tyrosine Kinase KIT: A New Look for an Old Receptor

Receptor tyrosine kinases (RTKs) control various signalling pathways in cells. Their remarkable conformational plasticity enables the specific recognition of many molecules such as ligands, substrates or proteins. In solution, RTKs are in equilibrium between different conformations ranging from an inactive auto-inhibited state to a fully active state. Ligandinduced activation of RTKs leads to the recruitment and activation of multiple downstream signalling proteins carrying the signal to the nucleus, where it alters the transcription patterns of genes that govern various aspects of cell physiology [1]. The explicit elucidation of signalling events is an important and unresolved problem in cell biology. The initiation of these cascade-like processes involves different domains of RTK, each of them performs its own specific actions, which are finely concerted by a tightly regulated allosteric mechanism that controls all functional processes [2]. Aberrant regulation of RTKs signalling networks is associated with the progression of many diseases. Focusing on the RTK KIT, an important target in oncology (leukaemia, mastocytosis, melanoma, gastrointestinal stromal tumour, and stomach cancers) [3], we first explain its physiological and mutation-induced activation [4]. Next, we will discuss KIT as a key starter/regulator of intracellular signalling which is mediated by regions possessing multiple phosphorylation sites. Since these regions are very flexible or disordered, they are not well understood yet. We present the first structural model of the full-length cytoplasmic domain of KIT, which contains all regions involved in post-transduction processes, phosphorylation and binding of intracellular protein [5] (Figure 1).