title: Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas.
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.
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Looyenga
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Dykema
authors.forename: Julie
authors.initials: J
authors.lastname: Koeman
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Swiatek
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
authors.forename: James H
authors.initials: JH
authors.lastname: Resau
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: MacKeigan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D017978:Receptors, Growth Factor; D000255:Adenosine Triphosphate; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases