BRI2 Processing and Its Neuritogenic Role Are Modulated by Protein Phosphatase 1 Complexing.

BRI2 is a ubiquitously expressed type II transmembrane phosphoprotein. BRI2 undergoes proteolytic processing into secreted fragments and during the maturation process it suffers post-translational modifications. Of particular relevance, BRI2 is a protein phosphatase 1 (PP1) interacting protein, where PP1 is able to dephosphorylate the former. Further, disruption of the BRI2:PP1 complex, using BRI2 PP1 binding motif mutants, leads to increased BRI2 phosphorylation levels. However, the physiological function of BRI2 remains elusive; although findings suggest a role in neurite outgrowth and neuronal differentiation. In the work here presented, BRI2 expression during neuronal development was investigated. This increases during neuronal differentiation and an increase in its proteolytic processing is also evident. To elucidate the importance of BRI2 phosphorylation for both proteolytic processing and neuritogenesis, SH-SY5Y cells were transfected with the BRI2 PP1 binding motif mutant constructs. For the first time, it was possible to show that BRI2 phosphorylation is an important regulatory mechanism for its proteolytic processing and its neuritogenic role. Furthermore, by modulating BRI2 processing using an ADAM10 inhibitor, a dual role for BRI2 in neurite outgrowth is suggested: phosphorylated full-length BRI2 appears to be important for the formation of neuritic processes, and BRI2 NTF promotes neurite elongation. This work significantly contributed to the understanding of the physiological function of BRI2 and its regulation by protein phosphorylation. J. Cell. Biochem. 118: 2752-2763, 2017.