The fibrillin‐1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR‐1208

Fibrillin‐1 is an extracellular matrix protein which contains one conserved RGD integrin‐binding motif. It constitutes the backbone of microfibrils in many tissues, and mutations in fibrillin‐1 cause various connective tissue disorders. Although it is well established that fibrillin‐1 interacts with several RGD‐dependent integrins, very little is known about the associated intracellular signaling pathways. Recent published evidence identified a subset of miRNAs regulated by fibrillin‐1 RGD‐cell adhesion, with miR‐1208 among the most downregulated. The present study shows that the downregulated miR‐1208 controls fibroblast proliferation. Inhibitor experiments revealed that fibrillin‐1 RGD suppressed miR‐1208 expression via c‐Src kinase and the downstream JNK signaling. Bioinformatic prediction and experimental target sequence validation demonstrated four miR‐1208 binding sites on the ERK2 mRNA and one on the MEK1 mRNA. ERK2 and MEK1 are critical proliferation‐promoting kinases. Decreased miR‐1208 levels elevated the total and phosphorylated ERK1/2 and MEK1/2 protein levels and the phosphorylated to total ERK1/2 ratio. Together, the data demonstrate a novel outside‐in signaling mechanism explaining how fibrillin‐1 RGD‐cell binding regulates fibroblast proliferation.