Biochimica et Biophysica Acta, 1155 (1993) 357-371 357 © 1993 Elsevier Science Publishers B.V. All rights reserved 0304-419X/93/$06.00 BBACAN 87280 Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product Jeffrey S. Rubin *, Donald P. Bottaro and Stuart A. Aaronson 1 Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892 (USA) (Received 27 September 1993) Contents I. Introduction .............................................................. 357 II. HGF/SF ................................................................ 358 A. Purification and physical properties ........................................... 358 B. Biological activities ....................................................... 358 C. cDNA cloning .......................................................... 359 1. Gene structure and chromosomal localization .................................. 359 2. Alternative mRNA transcripts ............................................. 361 D. Structure/function analysis ................................................. 361 E. Distribution and regulation of expression ....................................... 362 III. The HGF/SF receptor ...................................................... 363 A. Identification ........................................................... 363 B. The c-met proto-oncogene ................................................. 363 C. Regulation of c-Met activity................................................. 364 D. Post-receptor signal transduction ............................................. 365 IV. Broad perspectives .......................................................... 365 A. HGF/SF- and c-Met-related molecules ........................................ 365 B. Clinical relevance ........................................................ 366 C. Summary and future directions .............................................. 367 Acknowledgement ............................................................. 367 References .................................................................. 367 I. Introduction Cellular proliferation, migration, differentiation and programmed cell death all participate in the develop- ment and maintenance of multicellular organisms. These processes require coordinated interactions be- tween multiple cell types and are often mediated by polypeptide growth factors acting in either an au- tocrine or paracrine fashion. The identification of these growth factors and the biochemical pathways responsi- * Corresponding author. Fax: + 1 (301) 4968479. 1 Present address: Derald H. Runenberg Cancer Center, Mount Sinai Medical Center, 1 Gustave L. Levy Place, P.O. Box 1130, New York, NY 10029. ble for the transduction and implementation of their signals are essential first steps toward an understand- ing of growth control. The specific targeting of growth factor action is accomplished by the expression of high-affinity recep- tors in responsive cells. High-affinity binding between growth factor and receptor improves the probability of interaction, which is particularly important as growth factors are frequently found at low concentrations. Growth factor receptors generally possess three func- tionally distinct domains: an extracellular domain which contains the growth factor binding site, a transmem- brane region which anchors the receptor to the cell surface, and an intracellular domain which can interact with other intracellular molecules and thereby activate