Regulation of the extrinsic apoptotic pathway by the extracellular matrix glycoprotein EMILIN2.
Elastin microfibril interface-located proteins (EMILINs) constitute a family of extracellular matrix (ECM) glycoproteins characterized by the presence of an EMI domain at the N terminus and a gC1q domain at the C terminus. EMILIN1, the archetype molecule of the family, is involved in elastogenesis and hypertension etiology, whereas the function of EMILIN2 has not been resolved. Here, we provide evidence that the expression of EMILIN2 triggers the apoptosis of different cell lines. Cell death depends on the activation of the extrinsic apoptotic pathway following EMILIN2 binding to the TRAIL receptors DR4 and, to a lesser extent, DR5. Binding is followed by receptor clustering, colocalization with lipid rafts, death-inducing signaling complex assembly, and caspase activation. The direct activation of death receptors by an ECM molecule that mimics the activity of the known death receptor ligands is novel. The knockdown of EMILIN2 increases transformed cell survival, and overexpression impairs clonogenicity in soft agar and three-dimensional growth in natural matrices due to massive apoptosis. These data demonstrate an unexpected direct and functional interaction of an ECM constituent with death receptors and discloses an additional mechanism by which ECM cues can negatively affect cell survival.
Mongiat
Maurizio
M
Department of Molecular Oncology and Translational Research, Experimental Division 2, CRO-IRCCS, Aviano, Italy.
Ligresti
Giovanni
G
Marastoni
Stefano
S
Lorenzon
Erica
E
Doliana
Roberto
R
Colombatti
Alfonso
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011498:Protein Precursors / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C426245:EMILIN2 protein, human; D006023:Glycoproteins; D011498:Protein Precursors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases
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