From Vascular Smooth Muscle Cells to Folliculogenesis: What About Vasorin?

Abstract

First described in 1988, vasorin (VASN) is a transmembrane glycoprotein expressed during early mouse development, and with a less extent, in various organs and tissues (e.g., kidney, aorta, and brain) postnatally. Vasn KO mice die after 3 weeks of life from unknown cause(s). No human disease has been associated with variants of this gene so far, but VASN seems to be a potential biomarker for nephropathies and tumorigenesis. Its interactions with the TGF-β and Notch1 pathways offer the most serious assumptions regarding VASN functions. In this review, we will describe current knowledge about this glycoprotein and discuss its implication in various organ pathophysiology.

Keywords: Notch1; Slitl2; TGF-β; biomarker; development; pathophysiology.

Figure 1

(A) Vasorin 3D structure: Cartoon representation of the structure model of Vasn predicted by RaptorX (http://raptorx.uchicago.edu/). It is represented in rainbow color from the N-terminus to the C-terminus, at the exception of the predicted signal peptide (http://www.cbs.dtu.dk/services/SignalP/) colored in purple. The transmembrane fragment predicted by TMHMM (http://www.cbs.dtu.dk/services/TMHMM/) is localized at its place on the schematic membrane. The different predicted domains are indicated along the structure. The intracellular carboxy-terminal peptide with unknown structure is represented with a dotted line (4). (B) Vasorin major pathways: Vasn was first described as an inhibitor of TGF-β pathway: the metalloprotease ADAM 17 cleaves VASN and releases the soluble extracellular part of vasorin (sVASN). TGF-β binds to sVASN instead of TGFβRII. The hetero-tetrameric complex between TGF-β1 and−2 is not formed and the sequence of intra-cellular phosphorylation does not occur [adapted from (5)]. A second pathway was recently discovered showing that Notch1 can be stabilized at the membrane by VASN, thus escaping Numb (an inhibitor of the activation of Notch signaling) mediated endocytosis and lysosomal degradation. This bonding allows both extracellular cleavage by ADAM 10/17 and intracellular cleavage by the gamma secretase to cleave Notch1 intracellular peptide NICD1, which translocates to the nucleus to form a transcription complex [adapted from (6)].