Ephrin-B2 controls PDGFRβ internalization and signaling

Akiko Nakayama, Masanori Nakayama, Christopher J. Turner, Susanne Höing, John J. Lepore, Ralf H. Adams

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

B-class ephrins, ligands for EphB receptor tyrosine kinases, are critical regulators of growth and patterning processes in many organs and species. In the endothelium of the developing vasculature, ephrin-B2 controls endothelial sprouting and proliferation, which has been linked to vascular endothelial growth factor (VEGF) receptor endocytosis and signaling. Ephrin-B2 also has essential roles in supporting mural cells (namely, pericytes and vascular smooth muscle cells [VSMCs]), but the underlying mechanism is not understood. Here, we show that ephrin-B2 controls platelet-derived growth factor receptor β (PDGFRβ) distribution in the VSMC plasma membrane, endocytosis, and signaling in a fashion that is highly distinct from its role in the endothelium. Absence of ephrin-B2 in cultured VSMCs led to the redistribution of PDGFRβ from caveolin-positive to clathrin-associated membrane fractions, enhanced PDGF-B-induced PDGFRβ internalization, and augmented downstream mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK) activation but impaired Tiam1-Rac1 signaling and proliferation. Accordingly, mutant mice lacking ephrin-B2 expression in vascular smooth muscle developed vessel wall defects and aortic aneurysms, which were associated with impaired Tiam1 expression and excessive activation of MAP kinase and JNK. Our results establish that ephrin-B2 is an important regulator of PDGFRβ endocytosis and thereby acts as a molecular switch controlling the downstream signaling activity of this receptor in mural cells.

Original languageEnglish
Pages (from-to)2576-2589
Number of pages14
JournalGenes and Development
Volume27
Issue number23
DOIs
Publication statusPublished - Dec 1 2013
Externally publishedYes

Keywords

  • PDGF
  • Receptor
  • Signaling
  • Tyrosine kinase

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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