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Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas.

Publication ,  Journal Article
Looyenga, BD; Furge, KA; Dykema, KJ; Koeman, J; Swiatek, PJ; Giordano, TJ; West, AB; Resau, JH; Teh, BT; MacKeigan, JP
Published in: Proc Natl Acad Sci U S A
January 25, 2011

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 25, 2011

Volume

108

Issue

4

Start / End Page

1439 / 1444

Location

United States

Related Subject Headings

  • Thyroid Neoplasms
  • Signal Transduction
  • Receptors, Growth Factor
  • RNA Interference
  • Proto-Oncogene Proteins c-met
  • Protein Serine-Threonine Kinases
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Kidney Neoplasms
  • In Situ Hybridization, Fluorescence
  • Immunohistochemistry
 

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Looyenga, B. D., Furge, K. A., Dykema, K. J., Koeman, J., Swiatek, P. J., Giordano, T. J., … MacKeigan, J. P. (2011). Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proc Natl Acad Sci U S A, 108(4), 1439–1444. https://doi.org/10.1073/pnas.1012500108
Looyenga, Brendan D., Kyle A. Furge, Karl J. Dykema, Julie Koeman, Pamela J. Swiatek, Thomas J. Giordano, Andrew B. West, James H. Resau, Bin T. Teh, and Jeffrey P. MacKeigan. “Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas.Proc Natl Acad Sci U S A 108, no. 4 (January 25, 2011): 1439–44. https://doi.org/10.1073/pnas.1012500108.
Looyenga BD, Furge KA, Dykema KJ, Koeman J, Swiatek PJ, Giordano TJ, et al. Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1439–44.
Looyenga, Brendan D., et al. “Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas.Proc Natl Acad Sci U S A, vol. 108, no. 4, Jan. 2011, pp. 1439–44. Pubmed, doi:10.1073/pnas.1012500108.
Looyenga BD, Furge KA, Dykema KJ, Koeman J, Swiatek PJ, Giordano TJ, West AB, Resau JH, Teh BT, MacKeigan JP. Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1439–1444.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 25, 2011

Volume

108

Issue

4

Start / End Page

1439 / 1444

Location

United States

Related Subject Headings

  • Thyroid Neoplasms
  • Signal Transduction
  • Receptors, Growth Factor
  • RNA Interference
  • Proto-Oncogene Proteins c-met
  • Protein Serine-Threonine Kinases
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Kidney Neoplasms
  • In Situ Hybridization, Fluorescence
  • Immunohistochemistry