Met Receptor Tyrosine Kinase: Enhanced Signaling Through Adapter Proteins

Oncogene (2000) 19, 5582 ± 5589 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Met receptor tyrosine kinase: enhanced signaling through adapter proteins Kyle A Furge1, Yu-Wen Zhang1 and George F Vande Woude*,1 1Van Andel Research Institute, 333 Bostwick, N.E., Grand Rapids, Michigan, MI 49503, USA The Met receptor tyrosine kinase is the prototypic matrix (`invasion') (Jeers et al., 1996c; Matsumoto et member of a small subfamily of growth factor receptors al., 1994; Rong et al., 1994; Weidner et al., 1990). In that when activated induce mitogenic, motogenic, and addition, HGF/SF-Met signaling can induce several morphogenic cellular responses. The ligand for Met is dierent epithelial and mesenchymal cell types to hepatocyte growth factor/scatter factor (HGF/SF) and undergo an involved dierentiation program termed while normal HGF/SF-Met signaling is required for branching morphogenesis when the cells are grown in a embryonic development, abnormal Met signaling has three dimensional matrix (Brinkmann et al., 1995; been strongly implicated in tumorigenesis, particularly in Jeers et al., 1996c; Montesano et al., 1991a; Niemann the development of invasive and metastatic phenotypes. et al., 1998). During branching morphogenesis, groups Following ligand binding and autophosphorylation, Met of cells proliferate, migrate, and dierentiate to form a transmits intercellular signals using a unique multi- connected series of tubules arranged like branches from substrate docking site present within the C-terminal a tree. However, even in the absense of a three end of the receptor. The multisubstrate docking site dimensional matrix, signaling through the Met receptor mediates the binding of several adapter proteins such as can induce morphogenesis and lumen formation in Grb2, SHC, Crk/CRKL, and the large adapter protein certain cell types (Jeers et al., 1996a; Tsarfaty et al., Gab1. These adapter proteins in turn recruit several 1992). signal transducing proteins to form an intricate signaling In vivo, Met expression is predominately found in complex. Analysis of how these adapter proteins bind to cells of epithelial origin while HGF/SF expression is the Met receptor and what signal transducers they usually restricted to ®broblasts and stromal cells in the recruit have led to more substantial models of HGF/SF- surrounding mesenchyme (Sonnenberg et al., 1993). Met signal transduction and have uncovered new Several aspects of organogenesis such as tissue growth potential pathways that may be involved into Met and morphogenic dierentiation are regulated by mediated tumor cell invasion and metastasis. Oncogene interactions between the organ epithelia and the (2000) 19, 5582 ± 5589. surrounding mesenchyme. As such, paracrine signaling between HGF/SF and Met is believed play an Keywords: receptor tyrosine kinase; signal transduc- important role in regulating these epithelial-mesench- tion; c-Met; hepatocyte growth factor/scatter factor; yme interactions (Tsarfaty et al., 1994). In vivo, Met HGF/SF and HGF/SF likely play a key role in regulating many aspects of embryonic development including kidney and mammary gland formation (Santos et al., 1994; Introduction Soriano et al., 1995; Woolf et al., 1995; Yang et al., 1995), migration/development of muscle and neuronal Induction of several biological activities critical for precursors (Bladt et al., 1995; Streit et al., 1995), and development and maintenance of normal cellular liver and placenta organogenesis (Schmidt et al., 1995; functions such as proliferation, motility, survival, and Uehara et al., 1995). HGF/SF-Met signaling also dierentiation are mediated by protein growth factors promotes angiogenesis (Bussolino et al., 1992; Grant and their associated receptor tyrosine kinases. The Met et al., 1993) and has been described to facilitate wound receptor tyrosine kinase (RTK) was discovered as an healing (Nusrat et al., 1994) and tissue regeneration activated oncogene (Cooper et al., 1984; Park et al., (Matsumoto and Nakamura, 1993). 1986). The growth factor that binds and activates Met While normal HGF/SF-Met signaling is involved in is commonly named HGF/SF as it was identi®ed many aspects of embryogenesis, abnormal HGF/SF- independently as both a growth factor for hepatocytes Met signaling has been implicated in both tumor (HGF) and a ®broblast-derived cell motility factor, development and progression (Jeers et al., 1996d). In scatter factor (SF) (Bottaro et al., 1991; Nakamura et particular, HGF/SF-Met signaling was shown to play a al., 1984; Stoker and Perryman, 1985). Consistent with signi®cant role in promoting tumor cell invasion and the idea that this receptor-growth factor pair can metastasis (Rong et al., 1994). Recently, Met mutations induce dierent cellular responses depending on the have been identi®ed in patients with papillary renal cellular context, activation of Met by HGF/SF in vitro carcinoma, metastatic head and neck squamous cell leads to increased hepatocyte, renal tubule cell, and carcinomas, and isolated cases of ovarian cancer and endothelial cell proliferation (Bussolino et al., 1992; early-onset hepatocellular carcinoma (Schmidt et al., Kan et al., 1991), stimulation of both cell dissociation 1997, 1998; Olivero et al., 1999; Di Renzo et al., 2000; and motility (`scattering') (Rosen et al., 1990), and Tanyi et al., 1999; Park et al., 1999). Point mutations stimulation of cell movement through the extracellular within Met, primarily mutations within the activation loop of the tyrosine kinase domain, can lead to constitutive Met activation. Constitutive Met activa- *Correspondence: GF Vande Woude tion can also arise from inappropriate expression of Met receptor signaling complex KA Furge et al 5583 HGF/SF in cells that have already expression Met (or (Chan et al., 1988), rat (Wallenius et al., 1997), vice-versa) forming an autocrine stimulatory loop chickens (Thery et al., 1995), frogs (Aberger et al., (Bellusci et al., 1994; Jeers et al., 1996b; Rahimi et 1997; Aoki et al., 1996) and puer ®sh (Cottage et al., al., 1998; Rong et al., 1992, 1994). Cell lines generated 1999), met family members are notably absent from the that express mutated Met receptors that mimic those genomes of the worm Caenorhabditis elegans and the found in human cancers or cell lines that express both fruit ¯y Drosophila melanogaster ((Rubin et al., 2000) Met and HGF/SF form tumors that are both highly and K Furge and G Vande Woude, unpublished invasive and metastatic (Jeers et al., 1997, 1998; Rong observations). The absence of Met homologs in worms et al., 1992, 1994). Additionally, several groups have and ¯ies curtails using these powerful genetic systems reported that Met and/or HGF/SF expression is to examine HGF/SF-Met signaling. Whether this increased in a variety of human tumors and often is absence indicates Met and its related receptor tyrosine associated with high tumor grade and poor prognosis kinases are exclusive to vertebrates awaits the sequen- (reviewed in Jeers et al., 1996d). Met likely activates cing eorts from additional species. similar signal transduction pathways to promote invasive growth both during embryonic development Met signal transduction and tumor progression. Therefore, insights into the signaling requirements for either one of these events Met was originally identi®ed following the isolation of will likely be applicable to both. As it is now well a transforming cDNA fragment from a chemically established that receptor tyrosine kinases stimulate treated human osteosarcoma cell line (Cooper et al., various signal transduction pathways by organizing 1984; Park et al., 1986). In these cells, a chromosome large signaling complexes proximal to the receptor rearrangement fused a region of chromosome 1 called following growth factor stimulation, this review will tpr (for translocated promoter region) encoding a focus on some of the critical components of the Met leucine-zipper dimerization motif with the C-terminal signaling complex(s) and how these components are tyrosine kinase domain of met found on chromosome 7 recruited to the activated receptor. (Dean et al., 1987; Rodrigues and Park, 1993). The resulting oncoprotein, Tpr-Met, has high constitutive tyrosine kinase activity and can potently transform c-Met and related RTKs cells in vitro. Isolation of the tpr-met cDNA led to the The Met tyrosine kinase is the prototypic member of a identi®cation of the full-length met receptor (Park et small subfamily of RTKs that can induce proliferation, al., 1986). In wild-type cells, the primary met transcript cell movement, and morphogenic dierentiation in produces a 150 kD polypeptide that undergoes partial several dierent cell types (Brinkmann et al., 1995; glycosylation to produce a 170 kD precursor protein Jeers et al., 1996b,c; Medico et al., 1996; Montesano (Faletto et al., 1992; Gonzatti-Haces et al., 1986). et al., 1991b; Santoro et al., 1996). The growth factors p170Met is further glycosylated and cleaved into a that bind and activate members of the Met receptor 50 kD a-chain and a 140 kD b-chain. The a-subunit of subfamily are sometimes called plasminogen-related the mature, di-sul®de linked, a-b Met heterodimer is growth factors (PRGFs) since they all are large highly glycosylated and entirely extracellular while the proteins (*100 kD) that have a domain structure b-subunit contains a large extracellular region, a similar to the blood protease plasminogen (Gherardi et membrane spanning segment, and an intracellular

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