A HOMEO-INTERACTION SEQUENCE IN THE ECTODOMAIN OF THE FIBROBLAST GROWTH-FACTOR RECEPTOR

Interaction of fibroblast growth factor receptors (FGFR) sufficient fo r a trans-phosphorylation event in which one intracellular domain is s ubstrate for the other is essential for signal transduction. By analys is of the direct interaction of recombinant constructions coexpressed in baculoviral-infected insect cells, we identified a 17-amino acid se quence that is required for the stable interaction between ectodomains of FGFR, The sequence (160)ERSPHRPILQAGLPANK(176) (Glu(160)-Lys(176)) connects immunoglobulin modules II and III. In insect cells, the inte raction between Glu(160)-Lys(176) domains occurs independently of inta ct heparin or FGF binding domains, The sequence is not required for th e 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 Glu(160)-Lys(176) in the ectodoma in contributes to the interaction between intracellular domains in mam malian 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 p ropose that the Glu(160)-Lys(176) domain plays a pivotal role in restr iction of the interaction between kinases by pericellular matrix hepar an sulfate proteoglycan and divalent cations. Restrictions are overcom e by FGF or constitutively by diverse gain of function mutations which cause skeletal and craniofacial abnormalities.