The extracellular matrix protein EMILIN1 silences the RAS-ERK pathway via α4β1 integrin and decreases tumor cell growth.
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.
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Teresa Maria Elisa
TME
Modica
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Orlando
O
Maiorani
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Giulio
G
Sartori
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Eliana
E
Pivetta
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Roberto
R
Doliana
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Alessandra
A
Capuano
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Alfonso
A
Colombatti
Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy.
Paola
P
Spessotto
D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D015922:Complement C1q / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D039041:Integrin alpha4beta1; D008562:Membrane Glycoproteins; C030340:elastin microfibril interface located protein; D015922:Complement C1q; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins
RAS-ERK pathway; extracellular matrix; gC1q domain; proliferation; α4β1 integrin