Oncotarget

Research Papers:

The extracellular matrix protein EMILIN1 silences the RAS-ERK pathway via α4β1 integrin and decreases tumor cell growth

Teresa Maria Elisa Modica, Orlando Maiorani, Giulio Sartori, Eliana Pivetta, Roberto Doliana, Alessandra Capuano, Alfonso Colombatti _ and Paola Spessotto

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Oncotarget. 2017; 8:27034-27046. https://doi.org/10.18632/oncotarget.15067

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Abstract

Teresa Maria Elisa Modica1, Orlando Maiorani1, Giulio Sartori1, Eliana Pivetta1, Roberto Doliana1, Alessandra Capuano1, Alfonso Colombatti1, Paola Spessotto1

1Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.

Correspondence to:

Alfonso Colombatti, email: acolombatti@cro.it

Keywords: extracellular matrix, gC1q domain, α4β1 integrin, RAS-ERK pathway, proliferation

Abbreviations: ECM, extracellular matrix

Received: October 26, 2016    Accepted: January 09, 2017    Published: February 03, 2017

ABSTRACT

The extracellular matrix plays a fundamental role in physiological and pathological proliferation. It exerts its function through a signal cascade starting from the integrins that take direct contact with matrix constituents most of which behave as pro-proliferative clues. On the contrary, EMILIN1, a glycoprotein interacting with the α4β1 integrin through its gC1q domain, plays a paradigmatic anti-proliferative role. Here, we demonstrate that the EMILIN1-α4 interaction de-activates the MAPK pathway through HRas. Epithelial cells expressing endogenous α4 integrin and persistently plated on gC1q inhibited pERK1/2 increasing HRasGTP and especially the HRasGTP ubiquitinated form (HRasGTP-Ub). The drug salirasib reversed this effect. In addition, only the gC1q-ligated α4 integrin chain co-immunoprecipitated the ubiquitinated HRas. Only epithelial cells transfected with the wild type form of the α4 integrin chain showed the EMILIN1/α4β1/HRas/pERK1/2 link, whereas cells transfected with a α4 integrin chain carrying a truncated cytoplasmic tail had no effect. In this study we unveiled the pathway activated by the gC1q domain of EMILIN1 through α4β1 integrin engagement and leading to the decrease of proliferation in an epithelial system.


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