cell adhesion molecules can activate FGF receptors. This interaction may be crucial to developmental processes that are regulated by adhesion.

Since the original, dramatic discovery by Townes andHoltfreter [1] that dissociated amphibian cells taken fromthe three germ layers will sort themselves out andcorrectly reaggregate, differential cell affinity - differen-tial adhesion - has been recognized as a major regulatorof morphogenetic processes. In the last decade or so,many cell-cell adhesion molecules have been identified,the two best-characterized families of which are thecalcium-dependent cadherins and the calcium-indepen-dent immunoglobulin-like cell adhesion molecules.Although the way these molecules function in reaggrega-tion experiments and in the maintenance of tissue mor-phology may be largely passive, cell adhesion moleculeshave also been implicated in instructive developmentalprocesses, in particular cell migration and axon guidance.The extension of neuronal processes is dependent on celladhesion molecules and has been well-studied in vitro.Cell-cell adhesion molecules that can stimulate neuriteoutgrowth include: neural cell adhesion molecule(NCAM); neural adhesion molecules L1 and F3/F11;myelin-associated glycoprotein (MAG); protein zero(P0); and neuronal (N-) cadherin. Some of these mol-ecules have been shown to promote the growth ofneuronal processes not simply by passive adhesion butactively, by signalling to the interior of the neuron [2].Some of the components of the signalling pathwayinduced by three of these adhesion molecules - L1,NCAM and N-cadherin - have been identified inprimary cultures of cerebellar neurons. Neurite out-growth is assayed by plating these neurons, which expressall three adhesion molecules, on a 'substrate' of fibroblastsexpressing individual adhesion molecules. The out-growth of neuronal processes is then measured in thepresence of antagonists of various known intracellularsignalling pathways. In this way, the activation of calciumchannels, diacylglycerol lipase and a protein tyrosinekinase have been identified as potential components ofthe signalling pathway that leads from adhesion to neuriteoutgrowth. Using combinations of antagonists andagonists, a possible temporal order for the activation ofthese signalling molecules has been established, with thetyrosine kinase being the earliest component of thesystem and the latest being the opening of N-type andL-type calcium channels [2,3].How do cell adhesion molecules signal across the cellmembrane? The ability of neurons to extend processeson the surfaces of cells expressing adhesion molecules isnot affected by reagents that inhibit several non-receptor,cytoplasmic tyrosine kinases: this suggests that thetyrosine kinase involved in signalling in response toadhesion molecules might be more closely related to thetransmembrane receptor tyrosine kinase family [2]. Now,evidence suggests that the tyrosine kinase receptors forfibroblast growth factors (FGFs) may be involved insignalling from some cell adhesion molecules.The first piece of evidence linking the FGF receptor tocell adhesion molecules came when Byers et al. [4] foundthat the three amino-acid sequence HAV (His-Ala-Val),which has been implicated in mediating homophilicinteractions between some cadherins, is also foundwithin the extracellular domains of FGF receptors.Topologically, the largest FGF receptor protein isoformshave the following structure: an amino-terminal signalsequence; three immunoglobulin-like (Ig) domains,which are numbered I to III in order of increasingproximity to the plasma membrane; and an acidic regionbetween Ig domains I and II, called the acid box. Eachalso has a transmembrane domain, and the cytoplasmicregion contains a tyrosine kinase domain split by an'insert' region (Fig. 1); FGF receptor isoforms lackingIg domain I and/or the acid box have also beendescribed, as have possible secreted isoforms (for moredetail see [5,6]). The HAV sequence is located betweenIg domains I and II, just carboxy-terminal to the acidbox (Fig. 1).More careful examination of this region of FGF receptor1 has revealed short sequences with additional homologyto cell adhesion molecules. One region is related to aparticular alternatively spliced isoform of NCAM, theso-called VASE (variant alternatively-spliced exon)isoform, which is the only isoform to contain the VASEexon; another FGF receptor sequence has similarity tothe neural cell adhesion molecule L1. The Ll-like andNCAM-like sequences overlap partially, and all threedomains lie within a 20 amino-acid stretch of thereceptor that has been called the CAM-homologydomain (Fig. 1). This homology between cell adhesionmolecules and a group of signalling growth-factorreceptors suggests that an FGF receptor might be thetyrosine kinase implicated early in the signalling pathwaythat is activated by these three cell adhesion moleculesand leads to neurite outgrowth. The activation ofcommon signalling pathways by L1, N-cadherin andNCAM suggests that they might transduce a signal to theinterior of the neuron by the same mechanism. The1158 © Current Biology 1994, Vol 4 No 12