Furin-, ADAM 10-, and γ-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of β-catenin's transcriptional activity

Several receptor protein tyrosine phosphatases (RPTPs) are cell adhesion molecules involved in homophilic interactions, suggesting that RPTP outside-in signaling is coupled to cell contact formation. However, little is known about the mechanisms by which cell density regulates RPTP function. We show that the MAM family prototype RPTP{kappa} is cleaved by three proteases: furin, ADAM 10, and {[gamma}-secretase. Cell density promotes ADAM 10-mediated cleavage and shedding of RPTP{kappa}. This is followed by {gamma}-secretase-dependent intramembrane proteolysis of the remaining transmembrane part to release the phosphatase intracellular portion (PIC) from the membrane, thereby allowing its translocation to the nucleus. When cells were treated with leptomycin B, a nuclear export inhibitor, PIC accumulated in nuclear bodies. PIC is an active protein tyrosine phosphatase that binds to and dephosphorylates {beta}-catenin, an RPTP{kappa} substrate. The expression of RPTP{kappa} suppresses {beta}-catenin's transcriptional activity, whereas the expression of PIC increases it. Notably, this increase required the phosphatase activity of PIC. Thus, both isoforms have acquired opposing roles in the regulation of {beta}-catenin signaling. We also found that RPTPmu, another MAM family member, undergoes {gamma}-secretase-dependent processing. Our results identify intramembrane proteolysis as a regulatory switch in RPTP{kappa} signaling and implicate PIC in the activation of {beta}-catenin-mediated transcription.