Editors' ChoiceCell Adhesion

Ninjurin Signals Release

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Science's STKE  25 Jul 2006:
Vol. 2006, Issue 345, pp. tw248
DOI: 10.1126/stke.3452006tw248

The Drosophila tracheal system presents a model for studying cell adhesion because the tracheal tubes are lined with a specialized extracellular matrix that is continuous with the exterior cuticle. For the flies to grow, therefore, they must molt this cuticle, which requires the cells to detach from the cuticle. Drosophila melanogaster only has two genes for matrix metalloproteinases (MMPs), and analysis of mutant flies showed that Mmp1 is required for proper detachment of tracheal cells from the cuticle. Zhang et al. found by yeast two-hybrid analysis using the substrate-binding domain of Mmp1 as bait that Mmp1 interacted with Ninjurin A (NijA), which is the fly homolog of the vertebrate Ninjurins (so-called because the expression of ninjurin-1 was induced by nerve injury). The interaction was specific to Mmp1, did not occur with Mmp2, and further was specific to the splice form 1 of Mmp1. NijA and Mmp1 were coimmunoprecipated from fly extracts and were colocalized in larval tracheal trunks. When NijA was overexpressed in S2 cells or if S2 cells were exposed to conditioned medium from NijA-expressing cells, cellular adherence to the substrate was inhibited. (Mmp1 and a low abundance of NijA are present in S2 cells.) When tissue inhibitor of metalloproteinases (TIMP) or a catalytically inactive form of Mmp1 was coexpressed with NijA in the S2 cells, cell adherence was restored, suggesting that cleavage of NijA by Mmp1 led to cell detachment. The N-terminal extracellular domain of NijA was sufficient to cause cell detachment, because expression of a secreted form of this domain even in the presence of TIMP inhibited cell adhesion. The authors propose that NijA acts as a cell detachment signaling molecule, not as a direct cell adhesion mediator, because knockdown of NijA in S2 cells did not prevent cell adhesion.

S. Zhang, G. M. Dailey, E. Kwan, B. M. Glasheen, G. E. Sroga, A. Page-McCaw, An MMP liberates the Ninjurin A ectodomain to signal a loss of cell adhesion. Genes Dev. 20, 1899-1910 (2006). [Abstract] [Full Text]

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