Martins Filipa, Serrano Joana B, Müller Thorsten, da Cruz E Silva Odete A B, Rebelo Sandra
Neuroscience and Signalling Laboratory, Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro 3810-193, Portugal.
Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Bochum 44801, Germany.
J Cell Biochem. 2017 Sep;118(9):2752-2763. doi: 10.1002/jcb.25925. Epub 2017 Apr 27.
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. © 2017 Wiley Periodicals, Inc.
BRI2是一种广泛表达的II型跨膜磷蛋白。BRI2经过蛋白水解加工形成分泌片段，在成熟过程中会发生翻译后修饰。特别相关的是，BRI2是一种与蛋白磷酸酶1（PP1）相互作用的蛋白，其中PP1能够使前者去磷酸化。此外，使用BRI2 PP1结合基序突变体破坏BRI2:PP1复合物会导致BRI2磷酸化水平升高。然而，BRI2的生理功能仍然难以捉摸；尽管有研究结果表明其在神经突生长和神经元分化中起作用。在本文所展示的工作中，研究了神经元发育过程中BRI2的表达情况。其在神经元分化过程中增加，并且其蛋白水解加工的增加也很明显。为了阐明BRI2磷酸化对蛋白水解加工和神经突生成的重要性，用BRI2 PP1结合基序突变体构建体转染了SH-SY5Y细胞。首次有可能表明，BRI2磷酸化是其蛋白水解加工及其神经突生成作用的重要调节机制。此外，通过使用ADAM10抑制剂调节BRI2加工过程，提示了BRI2在神经突生长中的双重作用：磷酸化的全长BRI2似乎对神经突的形成很重要，而BRI2 NTF促进神经突伸长。这项工作对理解BRI2的生理功能及其通过蛋白磷酸化的调节做出了重大贡献。《细胞生物化学杂志》118: 2752 - 2763, 2017。© 2017威利期刊公司
