tPA Activates LDL Receptor-Related Protein 1-Mediated Mitogenic Signaling Involving the p90RSK and GSK3[beta] Pathway

摘要

In renal fibrosis, interstitial fibroblasts have an increased proliferative phenotype, and the numbers of interstitial fibroblasts closely correlate with the extent of kidney damage. The mechanisms underlying proliferation and resulting expansion of the interstitium remain largely unknown. Here we define the intracellular signaling events by which tissue plasminogen activator (tPA) promotes renal interstitial fibroblast proliferation. tPA promoted the proliferation of renal interstitial fibroblasts independent of its protease activity. The mitogenic effect of tPA required Tyr4507 phosphorylation of the cytoplasmic tail of its receptor LDL receptor-related protein 1. tPA triggered sequential proliferative signaling events involving Erk1/2, p90RSK, GSK3[beta] phosphorylation, and cyclin D1 induction. Blockade of Erk1/2 activation or knockdown of p90RSK suppressed tPA-induced GSK3[beta] phosphorylation, cyclin D1 expression, and fibroblast proliferation. In contrast, expression of constitutively active Mek1 mimicked tPA in inducing GSK3[beta] phosphorylation and cyclin D1 expression. Ectopic overexpression of an uninhibitable GSK3[beta] mutant eliminated tPA-induced cyclin D1 expression. In the murine obstruction model, tPA deficiency reduced renal GSK3[beta] phosphorylation and induction of PCNA and FSP-1. These findings show that tPA induces Tyr4507 phosphorylation of LDL receptor-related protein 1, which in turn leads to the downstream phosphorylation of Erk1/2, p90RSK, and GSK3[beta], followed by the induction of cyclin D1 in murine interstitial fibroblasts. This study implicates tPA as a mitogen that promotes interstitial fibroblast proliferation, leading to expansion of these cells.