kuzbanian-mediated cleavage of Drosophila Notch

Abstract

Loss of Kuzbanian, a member of the ADAM family of metalloproteases, produces neurogenic phenotypes in Drosophila. It has been suggested that this results from a requirement for kuzbanian-mediated cleavage of the Notch ligand Delta. Using transgenic Drosophila expressing transmembrane Notch proteins, we show that kuzbanian, independent of any role in Delta processing, is required for the cleavage of Notch. We show that Kuzbanian can physically associate with Notch and that removal of kuzbanian activity by RNA-mediated interference in Drosophila tissue culture cells eliminates processing of ligand-independent transmembrane Notch molecules. Our data suggest that in Drosophila, kuzbanian can mediate S2 cleavage of Notch.

When cell biology meets development: endocytic regulation of signaling pathways

“…These intercellular interactions are mediated through Notch/LIN-12, a conserved transmembrane receptor. To activate Notch, transmembrane proteins of the DSL family (Delta, Serrate, Lag-2) bind to the Notch receptor, allowing Kuzbanian to cleave Notch extracellularly (Pan and Rubin 1997;Lieber et al 2002). This extracellular cleavage permits Presenilin proteins to cleave Notch intracellularly near the transmembrane domain (De Strooper et al 1999;Struhl and Greenwald 1999;Ye et al 1999).…”

The ADAM family

“…21,26,27 Recently, Zhang et al and Weber et al have reported that ADAM10 is essential for Notch-mediated signaling in the mouse cardiovascular system and epidermis, respectively. 28,29 During cardiovascular development in mice, flies and frogs, Notch activation inhibits cardiomyocyte formation.…”

“…19 Shortly after the protein was first described, it was shown to be genetically and biochemically required for the proteolytic cleavage and activity of Notch. 5,20,21 ADAM17, also known as TACE (TNFa-converting enzyme), was first shown to cleave Notch in an in vitro cell culture-based system. 22 Initial genetic and biochemical studies of ADAM10 and ADAM17 failed to clearly support either ADAM as the main effector of S2 proteolysis.…”

Differential response of primitive human CD34− and CD34+ hematopoietic cells to the Notch ligand Jagged-1

“…The Kuzbanian gene, which belongs to the a-disintegrin and metalloproteinase superfamily of metallopro-teinases, is one of several protease genes that play critical roles in both Notch receptor and ligand maturation, regulation and function. [34][35][36][37] These data suggest that AC133+CD34À cells have distinct Notch receptor expression, which may relate to differential responsiveness to the Notch ligands.…”