Twisted Signaling
Authors: Foley John F. 
Published: September 2007

Kit is a member of the type III family of receptor tyrosine kinases (RTKs), which includes the platelet-derived growth factor (PDGF) receptors, PDGF-α and PDGF-β, and the macrophage colony-stimulating factor (M-CSF) receptor. The extracellular ligand-binding domain (ectodomain) of Kit (and other type III RTKs) consists of five immunoglobulin (Ig)-like domains, numbered D1 to D5 (D5 being the most membrane-proximal), a single transmembrane domain, and a cytoplasmic region. The cytokine stem cell factor (SCF) exists as a homodimer and binds to two Kit receptor monomers to form a dimerized Kit receptor. As with other RTKs, dimerization of Kit results in intermolecular autophosphorylation of tyrosine residues in the cytoplasmic region of the receptor followed by protein tyrosine kinase activation. Yuzawa
et al
. solved the crystal structures of the complete ectodomain of Kit in both monomeric and SCF-bound homodimeric forms. These studies revealed that one member of the SCF dimer bound directly to the D1, D2, and D3 domains of a Kit receptor monomer. Binding of SCF did not result in any appreciable change in the orientation of these domains compared with those observed in the Kit receptor monomer. However, Kit dimerization was accompanied by a large shift in the orientation of the membrane-proximal D4 and D5 domains relative to each other, such that they were brought to within 15 Å of each other compared with an intermolecular distance of 75 Å between Kit monomers. This shift presumably results in conformational changes in the transmembrane and cytoplasmic regions that lead to receptor activation. Direct interactions between opposing D4 domains were mediated by the formation of two salt bridges across the axis of the Kit dimer. Sequence analyses have shown that residues involved in the formation of these salt bridges are highly conserved in the D4 regions of other type III RTKs and in RTKs from other families, such as the vascular endothelial growth factor (VEGF) receptor. Mutation of critical residues in the D4 domain required for salt bridge formation did not prevent Kit receptor dimerization but did interfere with Kit receptor signaling, as measured by Western blot analysis of human embryonic kidney cells transfected with Kit receptor mutants. Intermolecular interactions between D5 domains were indirect and may be mediated by water molecules. The authors found that some previously known gain-of-function mutations of Kit map to areas of the D5:D5 interface. These mutations may strengthen intermolecular interactions between Kit monomers to such an extent that SCF binding is not necessary for dimerization, leading to inappropriate Kit signaling. As discussed in commentary by Lemmon and Ferguson, this study provides important information on how SCF drives Kit receptor dimerization and explains how mutations in Kit (and other related receptors) lead to inactive or constitutively active receptors.

S. Yuzawa, Y. Opatowsky, Z. Zhang, V. Mandiyan, I. Lax, J. Schlessinger, Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor.
Cell
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[PubMed]

M. A. Lemmon, K. M. Ferguson, A new twist in the transmembrane signaling tool-kit.
Cell
130
, 213-215 (2007).
[PubMed]