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. © 2017 Wiley Periodicals, Inc.
Neuroscience and Signalling Laboratory, Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro 3810-193, Portugal.
Filipa
F
Martins
Neuroscience and Signalling Laboratory, Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro 3810-193, Portugal.
Joana B
JB
Serrano
Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Bochum 44801, Germany.
Thorsten
T
Müller
Neuroscience and Signalling Laboratory, Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro 3810-193, Portugal.
Odete A B
OAB
da Cruz E Silva
Neuroscience and Signalling Laboratory, Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro 3810-193, Portugal.
Sandra
0000-0002-5862-5797
S
Rebelo
D000072197:ADAM10 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D054645:Protein Phosphatase 1 / Q000235:genetics; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar
D048868:Adaptor Proteins, Signal Transducing; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D054645:Protein Phosphatase 1; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C542371:ADAM10 protein, rat
ADAM10; BRI2; NEURITOGENESIS; PROTEIN COMPLEXES; PROTEIN PHOSPHORYLATION; PROTEOLYTIC PROCESSING