Matricellular Protein Cyr61 Is a Key Mediator of Platelet‐derived Growth Factor‐induced Cell Migration

Abstract

PDGF, a potent chemoattractant, induces cell migration via MAPK and PI3K/Akt pathways. However, the downstream mediators are still elusive. In particular, the role of extracellular mediators is largely unknown. In this study, we identified that the matricellular protein Cyr61, which is de novo synthesized in response to PDGF stimulation, is the key downstream mediator of the ERK and JNK pathways, independent of p38 MAPK and AKT pathways, and thereby mediates PDGF‐induced smooth muscle cell (SMC) migration, but not proliferation. Our results revealed that when Cyr61 was newly synthesized by PDGF, it was promptly translocated to the extracellular matrix and physically interacted with plasma membrane integrins α6β1 and αvβ3. We further demonstrate that Cyr61 and integrins are integral components of the PDGF signaling pathway, via an “outside‐in” signaling route to activate intracellular focal adhesion kinase (FAK), leading to cell migration. Thus, this study provides the first evidence that PDGF‐induced endogenous extracellular matrix component Cyr61 is a key mediator in modulating cell migration by connecting intracellular PDGF‐ERK and JNK signals with integrin/FAK signaling. Therefore, extracellular Cyr61 convergence with growth factor signaling and integrin/FAK signaling is a new concept of growth factor‐induced cell migration. The discovered signaling pathway may represent an important therapeutic target in growth factor‐mediated cell migration/invasion‐related vascular diseases and tumorigenesis.