EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.

[en] MT4-MMP (MMP-17) is a GPI-anchored matrix metalloprotease expressed on the surface of cancer cells which promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein (Rb) inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGF- and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expression were correlated in human triple negative breast cancer specimens. Altogether our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation.

Disciplines :

Oncology

Author, co-author :

Paye, Alexandra ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

Truong, Alice ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

Yip, Cassandre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

Cimino, Jonathan ; Université de Liège - ULiège > Département de chimie (sciences) > Laboratoire de spectrométrie de masse (L.S.M.)

Blacher, Silvia ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Cataldo, Didier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, humaines et path.

Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique

Maquoi, Erik ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

COLLIGNON, Joëlle ; Centre Hospitalier Universitaire de Liège - CHU > Service d'oncologie médicale

More authors (4 more)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.

Publication date :

October 2014

Journal title :

Cancer Research

ISSN :

0008-5472

eISSN :

1538-7445

Publisher :

American Association for Cancer Research, Inc. (AACR), Baltimore, United States - Maryland

Volume :

Issue :

Pages :

6758-70

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 20 November 2014

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