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c-Met: Structure, functions and potential for therapeutic inhibition

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Abstract

Studies on signal transduction pathways have generated various promising molecular targets for therapeutic inhibition in cancer therapy. Receptor tyrosine kinases represent an important class of such therapeutic targets. c-Met is a receptor tyrosine kinase that has been shown to be overexpressed and/or mutated in a variety of malignancies. A number of c-Met activating mutations, many of which are located in the tyrosine kinase domain, have been detected in various solid tumors and have been implicated in invasion and metastasis of tumor cells. It is known that stimulation of c-Met via its natural ligand, hepatocyte growth factor (also known as scatter factor, HGF/SF) results in a plethora of biological and biochemical effects in the cell. Activation of c-Met signaling can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. In this review, the role of c-Met dysregulation in tumor progression and metastasis is discussed in detail with particular emphasis on c-Met mutations. Moreover, we summarize current knowledge on various pathways of c-Met signal transduction, highlighting the central role in the cytoskeletal functions. In this summary is included recent data in our laboratory indicating that phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells. Most importantly, current data on c-Met suggest that when mutated or overexpressed in malignant cells, c-Met would serve as an important therapeutic target.

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Authors and Affiliations

  1. Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, USA

    Patrick C. Ma, Gautam Maulik & Ravi Salgia

  2. Harvard Medical School, 44 Binney Street, Boston, MA, 02115

    Patrick C. Ma, Gautam Maulik & Ravi Salgia

  3. Department of Hematology/Oncology, Tufts-New England Medical Center, 750 Washington Street, Boston, MA, 02111

    Patrick C. Ma

  4. Sugen, Inc., 230 East Grand Avenue, South San Francisco, CA, 94080

    James Christensen

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  1. Patrick C. Ma
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Correspondence to Ravi Salgia.

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Ma, P.C., Maulik, G., Christensen, J. et al. c-Met: Structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 22, 309–325 (2003). https://doi.org/10.1023/A:1023768811842

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