Hepatocyte growth factor interacts with both heparan and dermatan sulphates, in addition to its specific signalling

Hepatocyte growth factor/scatter factor (HGF/SF) is a 90 kDa paracrine factor synthesised by mesenchymal cells. In the extracellular milieu it is proteolytically clipped, yielding a disulphide-linked heterodimer (60 kDa α chain and 30 kDa β chain). The mature processed molecule is biologically active upon epithelial and endothelial cells, and also haemopoietic progenitor cells, and appears to have a crucial inductive role in embryonic organ development and adult organ regeneration (for reviews see Matsumoto and Nakamura, 1996; Tamagnone and Comoglio, 1997). HGF/SF interacts with two distinct classes of cell surface binding sites. The highest affinity sites (KD 20-25 pM) are low in number on most normal cells (102-103 per cell) and correspond to the specific tyrosine kinase receptor, Met (Tajima et al., 1992). Met is also a heterodimer, comprising a transmembrane 145 kDa β chain and a wholly extracellular 50 kDa α chain. The second class of HGF/SF-binding sites are slightly lower in affinity (KD 0.2 nM) but much more numerous (≥104 per cell), and appear to correspond to heparan sulphate proteoglycans (HSPGs) (Naldini et al., 1991). Interaction is mediated by the heparan sulphate (HS) chains, and can be reproduced in vitro using purified HGF/SF and HS (Lyon et al., 1994a; Ashikari et al., 1995) with a KD 0.2-3 nM (Rahmoune et al., 1998b). HGF/SF-mediated dimerisation of Met, and consequent Met activation by autoand trans-phosphorylation, generates a unique multifunctional cytoplasmic docking site that is recognised by various SH2 domain transducer proteins (Bardelli et al., 1992; Ponzetto et al., 1994). These trigger multiple and diverse intracellular signalling pathways, giving rise to the pleiotropic biological responses of HGF/SF, namely cell proliferation, motility, angiogenesis, morphogenesis, invasiveness and protection from apoptosis. Evidence from studies of a chimaeric receptor, comprising the cytoplasmic/ transmembrane domains of Met fused to the ectodomain of the nerve growth factor receptor (Weidner et al., 1993), and also of agonist monoclonal antibodies to Met (Prat et al., 1998), demonstrate that the Met cytoplasmic domain can transduce all the signals required for expression of the full repertoire of HGF/SF activities. Aberrant signalling via HGF/SF-Met is believed to play a significant role in promoting the growth and invasion of human tumours (for a review see Jeffers et al., 1996). Recently we demonstrated that the glycosaminoglycan (GAG)-binding specificity of HGF/SF is unusual in that, as well as interacting with HS, it also displays a strong affinity in 1999 Journal of Cell Science 112, 1999-2009 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0374