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Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition

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Abstract

Receptor tyrosine kinases have become important therapeutic targets for anti-neoplastic molecularly targeted therapies. c-Met is a receptor tyrosine kinase shown to be over-expressed and mutated in a variety of malignancies. Stimulation of c-Met via its ligand hepatocyte growth factor also known as scatter factor (HGF/SF), leads to a plethora of biological and biochemical effects in the cell. There has been considerable knowledge gained on the role of c-Met–HGF/SF axis in normal and malignant cells. This review summarizes the structure of c-Met and HGF/SF and their family members. Since there are known mutations of c-Met in solid tumors, particularly in papillary renal cell carcinoma, we have summarized the various mutations and over-expression of c-Met known thus far. Stimulation of c-Met can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. The biological functions altered by c-Met are quite unique and described in detail. Along with biological functions, various signal transduction pathways, including the cytoskeleton are altered with the activation of c-Met–HGF/SF loop. We have recently shown the phosphorylation of focal adhesion proteins, such as paxillin and p125FAK in response to c-Met stimulation in lung cancer cells, and this is detailed here. Finally, c-Met when mutated or over-expressed in malignant cells serves as an important therapeutic target and the most recent data in terms of inhibition of c-Met and downstream signal transduction pathways is summarized.

Introduction

The c-Met receptor tyrosine kinase was originally identified as an oncogene activated in vitro after treatment of a human osteogenic sarcoma (HOS) cell line with a chemical carcinogen N-methyl-N′-nitro-N-nitrosoguanidine [1]. In the HOS cell line, the Met proto-oncogene (chromosome 7) was involved in a translocation that placed the translocated promoter region locus (TPR) on chromosome 1 just upstream of a portion of the Met gene [2]. The TPR–MET fusion protein contained constitutively active Met kinase activity. Isolation of the TPR–MET cDNA led to the identification of the full-length Met receptor. Since this original characterization of c-Met as a proto-oncogene, much has been learned about the normal structure and function of c-Met, and great interest currently surrounds the role of aberrant c-Met signaling in tumorigenesis, particularly in the development of the invasive and metastatic phenotypes.

Met serves as the high affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF), a disulfide-linked heterodimeric molecule produced predominantly by mesenchymal cells and acting primarily on Met-expressing epithelial cells in an endocrine and/or paracrine fashion [3]. HGF/SF is so named because it was identified independently as both a growth factor for hepatocytes and as a fibroblast-derived cell motility factor, or scatter factor. Signaling via the Met–HGF/SF pathway has been shown to lead to an array of cellular responses including proliferation (mitosis), scattering (motility), and branching morphogenesis. The cellular responses to c-Met stimulation by HGF/SF are important in mediating a wide range of biological activities including embryological development, wound healing, tissue regeneration, angiogenesis, growth, invasion, and morphogenic differentiation [4]. As several of these physiological processes are known to go awry during tumorigenesis and metastasis, Met–HGF/SF signaling has been identified to play a role in many human cancers.

c-Met mutations have been well-described in hereditary and sporadic human papillary renal carcinomas and have been reported in ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, and gastric cancer. c-Met is also over-expressed in both non-small cell lung cancer and small cell lung cancer cells. Since c-Met appears to play an important role in oncogenesis of a variety of tumors, various inhibition strategies have been employed to therapeutically target this receptor tyrosine kinase. This review will discuss these topics in detail but in no way is designed to be overall comprehensive. Where also possible for the reader, we have also referred recently published review articles, and apologize if we have not referred the original or other published papers on the subject.

Section snippets

Structure

The human Met (HGF receptor) gene is located on chromosome 7 band 7q21–q31 and spans more than 120 kb in length, consisting of 21 exons separated by 20 introns [5]. In wild-type cells, the primary Met transcript produces a 150 kDa polypeptide that is partially glycosylated to produce a 170 kDa precursor protein. This 170 kDa precursor is further glycosylated and then cleaved into a 50 kDa α-chain and a 140 kDa β-chain which are linked via disulfide bonds.

Met homologs have been found in several

The ligand HGF/SF

Hepatocyte growth factor (HGF) was originally identified as a potent mitogen for hepatocytes and purified as a disulfide-linked heterodimer consisting of a 62-kDa α-subunit and a 34 kDa β-subunit. The α-subunit (heavy) contains an N-terminal hairpin domain consisting of about 27 amino acids followed by four canonical kringle domains, which are 80-amino acid double-looped structures stabilized by three internal disulfide bridges [10], [12], [13]. Kringle domains are important for protein–protein

Alterations of Met–HGF/SF detected in various human cancers

Aberrant c-Met signaling has been described in a variety of human cancers [16]. Mutations in c-Met, over-expression of c-Met and/or HGF/SF, and expression of c-Met and HGF/SF by the same cell can all contribute to tumorigenesis [4], [17], [18]. Cell lines with uncontrolled c-Met activation via one of these mechanisms are both highly invasive and metastatic [4]. Increased c-Met and/or HGF/SF expression by human tumor cells is often associated with high tumor grade and poor prognosis [19]. We

Overview

HGF/SF–Met signaling has been shown to trigger a variety of cellular responses that vary based upon the cellular context. For example, in vitro studies have revealed that activation of c-Met by HGF/SF leads to hepatocyte, renal tubule cell, and endothelial cell proliferation, stimulation of cell dissociation and motility i.e. scattering, and stimulation of cell movement through the extracellular matrix, i.e. invasion [6], [18]. Furthermore, signaling via this pathway has been shown to induce

Signaling via the cytoskeleton

A large signaling complex is recruited to activated c-Met and includes the adapter proteins Grb2, SHC, Gab1, and Crk/CRKL and the signal transducers phosphotidylinositol-3-OH kinase (PI3K), the signal transducer and activator of transcription-3 (Stat3), phospholipase C-γ (PLC-γ), the Ras guanine nucleotide exchange factor son-of-sevenless (SOS), the Src kinase, and the SHP2 phosphatase. Interaction of c-Met with adapter proteins and signal transducers can occur directly via the multisubstrate

Potential inhibitors of the c-Met pathways

Because of the overwhelming evidence favoring the role of aberrant HGF/SF–Met signaling in the pathogenesis of various human cancers, endogenous and exogenous inhibitors of this signaling pathway have drawn much interest. Specific inhibitors may have important therapeutic potential for the treatment of cancers in which Met activity contributes to the invasive/metastatic phenotype. There is a strong precedence to develop inhibitors of receptor tyrosine kinases. Fruitful studies from STI 571

Conclusion

c-Met is a unique receptor tyrosine kinase that plays an important role in the pathogenesis of a variety of malignancies. There are a number of activating mutations identified as well as cancers identified with over-expression of this receptor. With the ligand HGF/SF stimulating c-Met, there are a range of biological effects in tumor cells including scattering, branching morphogenesis, cell motility, invasion, migration and eventual metastasis. The biochemical pathways regulating all of these

Acknowledgements

This work was supported by NIH Grant CA75348-05 and Lowe’s Center for Thoracic Oncology (RS).

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