title: The matricellular protein Cyr61 is a key mediator of platelet-derived growth factor-induced cell migration.
abstract: Platelet-derived growth factor (PDGF), a potent chemoattractant, induces cell migration via the 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 the matricellular protein Cyr61, which is de novo synthesized in response to PDGF stimulation, as the key downstream mediator of the ERK and JNK pathways, independent of the p38 MAPK and AKT pathways, and, thereby, it mediates PDGF-induced smooth muscle cell 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 the 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. Therefore, this study provides the first evidence that the 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.
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and the Department of Regenerative Medicine, College of Pharmacy, and.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and.
authors.forename: Feng
authors.initials: F
authors.lastname: Hao
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and College of Life Sciences, Jilin University, Changchun 130021, China.
authors.forename: Dong
authors.initials: D
authors.lastname: An
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zeng
authors.affiliation: the Department of Regenerative Medicine, College of Pharmacy, and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and cuim@utk.edu.
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000502:physiology*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D016023:Integrins; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Cyr61; Gene Expression; PDGF; Signal Transduction; Signaling; Vascular Biology; Vascular Smooth Muscle Cells