Potentiation of platelet-derived growth factor receptor-β signaling mediated by integrin-associated MFG-E8

Sei Ichiro Motegi, Susan Garfield, Xu Feng, Miklós Sárdy, Mark C. Udey

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Objective-: Pericytes/pericyte precursors produce milk fat globule-associated protein with epidermal growth factor and factor VIII-like domains (MFG-E8) in vivo, and this α v integrin ligand enhances angiogenesis in tumors and in oxygen-induced retinopathy in mice. Inhibition of MFG-E8 production or function attenuates platelet-derived growth factor-BB (PDGF-BB)-induced migration of pericyte/pericyte precursor-like 10T1/2 cells in vitro. Herein, we describe mechanisms by which MFG-E8 modulates PDGF-BB:PDGF receptor β (PDGFRβ) signaling in 10T1/2 cells. Methods and Results-: Small interfering RNA depletion of MFG-E8 from 10T1/2 cells or antibody inhibition of MFG-E8 action enhanced PDGF-BB-dependent degradation of PDGFRβ and attenuated signaling. Coimmunoprecipitation revealed transient association of MFG-E8 with PDGFRβ in PDGF-BB-treated 10T1/2 cells and reduced PDGFRβ-focal adhesion kinase association in MFG-E8-depleted cells. Confocal microscopy demonstrated that MFG-E8 binding to 10T1/2 cells was RGD motif and α v dependent but PDGF-BB treatment independent, whereas colocalization of MFG-E8 with PDGFRβ was enhanced by PDGF-BB. Ubiquitination of PDGFRβ was also increased in MFG-E8 small interfering RNA-transfected cells. Conclusion-: Integrin αv-bound MFG-E8 associates with PDGFRβ and focal adhesion kinase after PDGF-BB treatment, results in cell surface retention of PDGFRβ, delays receptor degradation, potentiates downstream signaling, and enhances migration of 10T1/2 cells. MFG-E8 may promote angiogenesis, in part, via cell autonomous actions on pericytes or pericyte precursors that result in enhanced PDGF-BB:PDGFRβ signaling mediated via integrin-growth factor receptor cross-talk.

Original languageEnglish
Pages (from-to)2653-2664
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number11
StatePublished - Nov 2011


  • MFG-E8
  • PDGF receptor β
  • integrin
  • pericyte


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