Revelations of the RYK receptor Michael M. Halford and Steven A. Stacker* Summary Significant progress has been made over the last decade in elucidating the mechanisms employed by receptor protein tyrosine kinases (RTKs) in transducing extra- cellular signals critical for the regulation of diverse cellular activities. Nevertheless, revealing the biological significance of a subset of the RTKs that contain catalytically inactive protein tyrosine kinase domains has proven more elusive. ErbB3 has served as the prototype for models of catalytically inactive RTK func- tion, performing the role of signal diversification in heterodimeric receptor complexes with other ErbB sub- family members. The receptor related to tyrosine kinases (RYK) is unique amongst the catalytically inactive RTKs. Based on structural or functional properties of the extracellular domain, RYK cannot be classified into an existing RTK subfamily. Recent genetic analyses of mouse Ryk and its Drosophila orthologue derailed have defined a role for this novel subfamily of receptors in the control of craniofacial development and neuronal path- way selection, respectively. Recent biochemical data lead us to propose a model that involves RYK in signal crosstalk and scaffold assembly with Eph receptors. This model is consistent with the established roles of Eph receptors and ephrins in craniofacial and nervous system morphogenesis. BioEssays 23:34±45, 2001. ß 2001 John Wiley & Sons, Inc. Introduction Eukaryotes express a wide variety of transmembrane proteins at the cell surface responsible for the transduction of regulatory information into the cell (receptors). Information transferred across the plasma membrane by receptors is integrated to elicit appropriate cellular responses to develop- mental and physiological cues present in the extracellular environment. Loss or gain of receptor function can therefore uncouple cell behavior from these extrinsic inputs, often with serious pathological consequences. (1) Type I, single-pass transmembrane proteins, which project a large glycosylated extracellular domain and possess a cytoplasmic portion containing a protein tyrosine kinase (PTK) domain, constitute the receptor protein tyrosine kinase (RTK) family. (2) Twelve conserved peptide sequence motifs, or subdomains, are the signature of the PTK catalytic domain and these involve some 13 invariant residues which fulfill vital structural or catalytic roles at the enzyme active site. (3,4) Members of the RTK family play cardinal roles in the control of a broad range of cellular activities, including metabolism (e.g. the insulin receptor), mitogenesis (e.g. the PDGF receptors), differentiation (e.g. the CSF-1 receptor), morphogenesis (e.g. Drosophila Torso), cell survival (e.g. the IGF-1 receptor), adhesion (e.g. Drosophila Trk), axon pathfinding (e.g. the Eph receptors), motility (e.g. the MET receptor) and oncogenesis (e.g. the ErbBs). Major advances in our understanding of the mechanisms of RTK activation by growth-factor-type ligands have developed over the last decade. (5±7) The primary function of growth factors is the clustering of receptor chains into homodimeric or heterodimeric complexes. (8) This is achieved by many stoichiometric variations on a common theme, (9,10) involving a ligand with multivalent receptor binding sites; either oligomeric growth factor (e.g. dimeric PDGF-A), or monomeric growth factor multimerized through association with acces- sory factors (e.g. FGF with heparan sulfate proteoglycans), or clustered cell surface-anchored ligands (e.g. transmembrane ephrin-B ligands clustered by submembranous PDZ domains) or monomeric growth factor containing tandemly repeated receptor-binding motifs (e.g. collagen), drive the cross-linking of two RTK monomers through their extracellular domains. The resulting allosteric juxtaposition of PTK domains in the cytoplasm is responsible for activation of receptor phospho- transferase activity. This highly complex event is incompletely understood, and involves release of the catalytic domain from autoinhibition (11) and conformational changes in the receptor intracellular domain. (12) 34 BioEssays 23.1 BioEssays 23:34±45, ß 2001 John Wiley & Sons, Inc. Ludwig Institute for Cancer Research, Australia. Funding agencies: The National Health and Medical Research Council of Australia and the Cooperative Research Centre for Cellular Growth Factors. M.M.H. is the recipient of an Anti-Cancer Council of Victoria Post-Doctoral Research Fellowship. *Correspondence to: Steven Stacker, Ludwig Institute for Cancer Research and Cooperative Research Centre for Cellular Growth Factors, PO Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia. E-mail: Steven.stacker@ludwig.edu.au Abbreviations: AF-6, ALL-1 fused gene from chromosome 6; ap, apterous; CSF-1R, colony stimulating factor-1 receptor; dpc, days post coitum; drl, derailed; eg, eagle; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; IGF-1, insulin-like growth factor-1; lio, linotte; LRR, leucine-rich repeat; MAPK, mitogen-activated protein kinase; NGF, nerve growth factor; NTR, neurotrophin receptor; PDGFR, platelet- derived growth factor receptor; PDZ, PSD95/ DlgA/ ZO-1; PTB, phosphotyrosine-binding; PTK, protein tyrosine kinase; PTPase, protein phosphotyrosyl phosphatase; RTK, receptor protein tyrosine kinase; RYK, receptor related to t yrosine kinases; SAM, sterile alpha motif; SH2, Src homology 2; SHP-1; Src homology 2 domain- containing PTPase-1; SHPS-1, SHP substrate-1; VEGFR-1, vascular endothelial growth factor receptor-1; WIF-1, Wnt inhibitory factor-1. Review articles