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5. Sequence-dependent trafficking and activity ofGDE2,a GPI-specific phospholipase promoting neuronal differentiation.

Author

Salgado-Polo, Fernando, van Veen, Michiel, van den Broek, Bram, Jalink, Kees, Leyton-Puig, Daniela, Perrakis, Anastassis, Moolenaar, Wouter H., and Matas-Rico, Elisa

Subjects
*NEURONAL differentiation, *C-terminal residues, *NEURAL stem cells, *GLYCOSYLPHOSPHATIDYLINOSITOL, *PHOSPHOLIPASES, *NEURODEGENERATION, *ENDOCYTOSIS
Abstract

GDE2 (also known as GDPD5) is a multispanning membrane phosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby promotes neuronal differentiation both in vitro and in vivo. GDE2 is a prognostic marker in neuroblastoma, while loss of GDE2 leads to progressive neurodegeneration in mice; however, its regulation remains unclear. Here, we report that, in immature neuronal cells, GDE2 undergoes constitutive endocytosis and travels back along both fast and slow recycling routes. GDE2 trafficking is directed by C-terminal tail sequences that determine the ability of GDE2 to cleave GPI-anchored glypican-6 (GPC6) and induce a neuronal differentiation program. Specifically, we define a GDE2 truncation mutant that shows aberrant recycling and is dysfunctional, whereas a consecutive deletion results in cellsurface retention and gain of GDE2 function, thus uncovering distinctive regulatory sequences. Moreover, we identify a C-terminal leucine residue in a unique motif that is essential for GDE2 internalization. These findings establish a mechanistic link between GDE2 neuronal function and sequence-dependent trafficking, a crucial process gone awry in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Published
2020
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7. Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells.

Author

van Veen, Michiel, Matas-Rico, Elisa, van de Wetering, Koen, Leyton-Puig, Daniela, Kedziora, Katarzyna M., De Lorenzi, Valentina, Stijf-Bultsma, Yvette, van den Broek, Bram, Jalink, Kees, Sidenius, Nicolai, Perrakis, Anastassis, Moolenaar, Wouter H., van Veen, Michiel, Matas-Rico, Elisa, van de Wetering, Koen, Leyton-Puig, Daniela, Kedziora, Katarzyna M., De Lorenzi, Valentina, Stijf-Bultsma, Yvette, van den Broek, Bram, Jalink, Kees, Sidenius, Nicolai, Perrakis, Anastassis, and Moolenaar, Wouter H.

Abstract

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior.

Published
2017

8. Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells

Author

van Veen, Michiel, primary, Matas-Rico, Elisa, additional, van de Wetering, Koen, additional, Leyton-Puig, Daniela, additional, Kedziora, Katarzyna M, additional, De Lorenzi, Valentina, additional, Stijf-Bultsma, Yvette, additional, van den Broek, Bram, additional, Jalink, Kees, additional, Sidenius, Nicolai, additional, Perrakis, Anastassis, additional, and Moolenaar, Wouter H, additional

Published
2017
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9. Author response: Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells

Author

van Veen, Michiel, primary, Matas-Rico, Elisa, additional, van de Wetering, Koen, additional, Leyton-Puig, Daniela, additional, Kedziora, Katarzyna M, additional, De Lorenzi, Valentina, additional, Stijf-Bultsma, Yvette, additional, van den Broek, Bram, additional, Jalink, Kees, additional, Sidenius, Nicolai, additional, Perrakis, Anastassis, additional, and Moolenaar, Wouter H, additional

Published
2017
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14. Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome

Author

Matas-Rico, Elisa, primary, van Veen, Michiel, additional, Leyton-Puig, Daniela, additional, van den Berg, Jeroen, additional, Koster, Jan, additional, Kedziora, Katarzyna M., additional, Molenaar, Bas, additional, Weerts, Marjolein J.A., additional, de Rink, Iris, additional, Medema, René H., additional, Giepmans, Ben N.G., additional, Perrakis, Anastassis, additional, Jalink, Kees, additional, Versteeg, Rogier, additional, and Moolenaar, Wouter H., additional

Published
2016
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