Tetraspanin CD37 Directly Mediates Transduction of Survival and Apoptotic Signals

SummaryTetraspanins are commonly believed to act only as “molecular facilitators,” with no direct role in signal transduction. We herein demonstrate that upon ligation, CD37, a tetraspanin molecule expressed on mature normal and transformed B cells, becomes tyrosine phosphorylated, associates with proximal signaling molecules, and initiates a cascade of events leading to apoptosis. Moreover, we have identified two tyrosine residues with opposing regulatory functions: one lies in the N-terminal domain of CD37 in a predicted “ITIM-like” motif and mediates SHP1-dependent death, whereas the second lies in a predicted “ITAM motif” in the C-terminal domain of CD37 and counteracts death signals by mediating phosphatidylinositol 3-kinase-dependent survival.

► CD37 is a tetraspanin directly involved in signal transduction
► CD37 possesses dual noncanonical ITIM and ITAM motifs that regulate cell death
► CD37 ligation mediates BIM-dependent mitochondrial apoptosis of CLL B cells