title: Posttranslational proteolytic processing of Leda-1/Pianp involves cleavage by MMPs, ADAM10/17 and gamma-secretase.
abstract: Leda-1/Pianp is a type I transmembrane protein expressed by CNS cells, murine melanoma cell line B16F10 and rat liver sinusoidal endothelial cells. The early steps of posttranslational modifications of Leda-1/Pianp have been described to include glycosylation and processing by proprotein convertases. Here, we comprehensively characterized the subsequent steps of proteolytic processing of Leda-1/Pianp. For this purpose specific protease inhibitors and cell lines deficient in PS1, PS2, PS1/PS2 and ADAM10/17 were deployed. Leda-1/Pianp was cleaved at numerous cleavage sites within the N-terminal extracellular domain. The sheddases involved included MMPs and ADAM10/17. Ectodomain shedding yielded C-terminal fragments (CTF) of ∼15 kDa. The CTF was further processed by the γ (gamma)-secretase complex to generate the intracellular domain (ICD) of ∼10 kDa. Although PS1 was the dominant intramembrane protease, PS2 was also able to cleave Leda-1/Pianp in the absence of PS1. Thus, Leda-1/Pianp is constitutively processed by proprotein convertases, sheddases including MMPs and ADAM10/17 and intramembrane protease γ-secretase.
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Siladitta
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Adrian
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Weber
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Evdokimov
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Winkler
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: cyrill.geraud@umm.de.
authors.forename: Cyrill
authors.initials: C
authors.lastname: Géraud
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism*; D000072198:ADAM17 Protein / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000502:physiology; D059748:Proteolysis; D013379:Substrate Specificity
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C557209:Pianp protein, mouse; C550858:Pianp protein, rat; D053829:Amyloid Precursor Protein Secretases; D020782:Matrix Metalloproteinases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein
keywords: ADAM; Gamma secretase; Immune regulation; Nervous system; Proteolysis