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Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells

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posted on 2016-02-23, 13:00 authored by G. Muharram, P. Sahgal, T. Korpela, N. De Franceschi, R. Kaukonen, Katherine Clark, D. Tulasne, O. Carpén, J. Ivaska
Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with β1-integrin cytoplasmic tail positively regulates β1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.

Funding

K.C. has been funded by the Wellcome Trust. P.S. is funded by the Turku Doctoral program of Molecular Medicine (TuDMM). This study has been supported by the Academy of Finland, an ERC Starting Grant, an ERC Consolidator Grant, the Sigrid Juselius Foundation, and the Finnish Cancer Organizations.

History

Citation

Developmental Cell, Volume 29, Issue 5, 9 June 2014, Pages 629-630

Version

  • VoR (Version of Record)

Published in

Developmental Cell

Publisher

Elsevier (Cell Press)

issn

1534-5807

eissn

1878-1551

Acceptance date

2014-03-31

Available date

2016-02-23

Publisher version

http://www.sciencedirect.com/science/article/pii/S1534580714001981

Notes

Supplemental Information includes Supplemental Experimental Procedures, six figures, one table, and two movies and can be found with this article online at http://dx.doi.org/10.1016/j.devcel.2014.03.024.

Language

en

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