A Homeo-interaction Sequence in the Ectodomain of the Fibroblast Growth Factor Receptor

Interaction of fibroblast growth factor receptors (FGFR) sufficient for a trans-phosphorylation event in which one intracellular domain is substrate for the other is essential for signal transduction. By analysis of the direct interaction of recombinant constructions co-expressed in baculoviral-infected insect cells, we identified a 17-amino acid sequence that is required for the stable interaction between ectodomains of FGFR. The sequence160ERSPHRPILQAGLPANK176(Glu160–Lys176) connects immunoglobulin modules II and III. In insect cells, the interaction between Glu160–Lys176 domains occurs independently of intact heparin or FGF binding domains. The sequence is not required for the binding of heparin or FGF-1, but is essential for mitogenic activity of the FGFR kinase in mammalian cells. The results support a model in which the homeo-interaction between Glu160–Lys176 in the ectodomain contributes to the interaction between intracellular domains in mammalian cell membranes (Kan, M., Wang, F., Kan, M., To, B., Gabriel, J. L., and McKeehan, W. L. (1996) J. Biol. Chem. 271, 26143–26148). We propose that the Glu160–Lys176 domain plays a pivotal role in restriction of the interaction between kinases by pericellular matrix heparan sulfate proteoglycan and divalent cations. Restrictions are overcome by FGF or constitutively by diverse gain of function mutations which cause skeletal and craniofacial abnormalities.