Cell Biology

BMPed into an Endocytic Sink Trap

Science Signaling  03 Mar 2009:
Vol. 2, Issue 60, pp. ec85
DOI: 10.1126/scisignal.260ec85

Binding of bone morphogenetic protein 4 (BMP4) to its receptor causes phosphorylation and activation of Smad transcription factors. Low concentrations of the secreted factor BMPER (BMP-binding endothelial cell precursor–derived regulator) enhance BMP4 activity, whereas high concentrations paradoxically inhibit it. Kelley et al. now provide evidence for a mechanism underlying the dual nature of this regulation. When added to mouse endothelial cells (MECs) at concentrations equimolar to BMP4, BMPER increased Smad activation over BMP4 alone. However, high concentrations of BMPER inhibited BMP4-mediated Smad activation by triggering endocytosis of both factors through a clathrin-mediated pathway that led to the lysosomal degradation of BMP4 and BMPER. This process required the proteolytic processing of BMPER into its mature form and the binding of BMP4 to its receptor. During embryogenesis, alveoli development requires the regression of lung mesenchyme through apoptosis, which the authors proposed occurs through BMPER inhibition of BMP4 signaling. Treatment of isolated mouse embryonic lung mesenchyme with BMP4 and low concentrations of BMPER promoted fibroblast survival, whereas high concentrations of BMPER increased apoptosis. Compared with wild-type mice, the lung tissue from BMPER+/– mice exhibited reduced apoptosis and elevated BMP4 activity, as measured by the expression of Id1 (inhibitor of differentiation or inhibitor of DNA binding 1), a downstream BMP target. Two other regulators of BMP signaling, Noggin or Gremlin, also attenuated BMP4-mediated Smad phosphorylation by triggering BMP4 endocytosis in MECs; however, Chordin did not inhibit Smad activity through BMP4 internalization. In addition, Noggin and Gremlin treatment prevented BMP4-mediated Smad phosphorylation regardless of whether BMPER was also present, and BMPER induced Chordin internalization and degradation only in the absence of BMP4, hinting at a complex hierarchy among BMP inhibitors.

R. Kelley, R. Ren, X. Pi, Y. Wu, I. Moreno, M. Willis, M. Moser, M. Ross, M. Podkowa, L. Attisano, C. Patterson, A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling. J. Cell Biol. 184, 597–609 (2009). [Abstract] [Full Text]