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The cytosolic domain of Notch is a membrane-tethered transcription factor. Ligand binding ultimately leads to gamma-secretase cleavage within the transmembrane domain, allowing the intracellular domain to translocate to the nucleus and activate target gene transcription. Constitutive Notch signaling has been associated with human cancers such as T cell acute lymphoblastic leukemia (T-ALL). As tetraspanins have been implicated in many different signaling processes, we assessed their potential contribution to Notch signaling. We used a genetic assay in Caenorhabditis elegans to identify TSP-12 as a positive factor for Notch activity in several cellular contexts. Then, using a cell culture system, we showed that two human TSP-12 orthologs, TSPAN33 and TSPAN5, promote Notch activity and are likely to act at the gamma-secretase cleavage step. We also acquired evidence for functional redundancy among tetraspanins in both C. elegans and human cells. Selective inhibition of tetraspanins may constitute an anti-NOTCH therapeutic approach to reduce gamma-secretase activity.

A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells