Abstract
The receptor tyrosine kinase MET is frequently amplified in human tumors, resulting in high cell surface densities and constitutive activation even in the absence of growth factor stimulation by its endogenous ligand, hepatocyte growth factor (HGF). We sought to identify mechanisms of signaling crosstalk that promote MET activation by searching for kinases that are coordinately dysregulated with wild-type MET in human tumors. Our bioinformatic analysis identified leucine-rich repeat kinase-2 (LRRK2), which is amplified and overexpressed in papillary renal and thyroid carcinomas. Down-regulation of LRRK2 in cultured tumor cells compromises MET activation and selectively reduces downstream MET signaling to mTOR and STAT3. Loss of these critical mitogenic pathways induces cell cycle arrest and cell death due to loss of ATP production, indicating that MET and LRRK2 cooperate to promote efficient tumor cell growth and survival in these cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Carcinoma, Papillary / genetics
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Carcinoma, Papillary / metabolism
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Carcinoma, Papillary / pathology
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Cell Cycle
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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Gene Amplification
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Immunoblotting
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-met / genetics*
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Proto-Oncogene Proteins c-met / metabolism
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RNA Interference
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Receptors, Growth Factor / genetics*
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Receptors, Growth Factor / metabolism
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Signal Transduction*
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / metabolism
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Thyroid Neoplasms / pathology
Substances
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Receptors, Growth Factor
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Adenosine Triphosphate
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MET protein, human
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Proto-Oncogene Proteins c-met
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LRRK2 protein, human
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Protein Serine-Threonine Kinases