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TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching

Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and increases in exocytic vesicle fusion, yet how these oc...

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Autores principales: Plooster, Melissa, Menon, Shalini, Winkle, Cortney C., Urbina, Fabio L., Monkiewicz, Caroline, Phend, Kristen D., Weinberg, Richard J., Gupton, Stephanie L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576901/
https://www.ncbi.nlm.nih.gov/pubmed/28701345
http://dx.doi.org/10.1091/mbc.E16-08-0594
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author Plooster, Melissa
Menon, Shalini
Winkle, Cortney C.
Urbina, Fabio L.
Monkiewicz, Caroline
Phend, Kristen D.
Weinberg, Richard J.
Gupton, Stephanie L.
author_facet Plooster, Melissa
Menon, Shalini
Winkle, Cortney C.
Urbina, Fabio L.
Monkiewicz, Caroline
Phend, Kristen D.
Weinberg, Richard J.
Gupton, Stephanie L.
author_sort Plooster, Melissa
collection PubMed
description Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and increases in exocytic vesicle fusion, yet how these occurrences are linked is unknown. Here we demonstrate that tripartite motif protein 9 (TRIM9)-dependent ubiquitination of DCC blocks the interaction with and phosphorylation of FAK. Upon netrin-1 stimulation TRIM9 promotes DCC multimerization, but TRIM9-dependent ubiquitination of DCC is reduced, which promotes an interaction with FAK and subsequent FAK activation. We found that inhibition of FAK activity blocks elevated frequencies of exocytosis in vitro and elevated axon branching in vitro and in vivo. Although FAK inhibition decreased soluble N-ethylmaleimide attachment protein receptor (SNARE)-mediated exocytosis, assembled SNARE complexes and vesicles adjacent to the plasma membrane increased, suggesting a novel role for FAK in the progression from assembled SNARE complexes to vesicle fusion in developing murine neurons.
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spelling pubmed-55769012017-11-16 TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching Plooster, Melissa Menon, Shalini Winkle, Cortney C. Urbina, Fabio L. Monkiewicz, Caroline Phend, Kristen D. Weinberg, Richard J. Gupton, Stephanie L. Mol Biol Cell Articles Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and increases in exocytic vesicle fusion, yet how these occurrences are linked is unknown. Here we demonstrate that tripartite motif protein 9 (TRIM9)-dependent ubiquitination of DCC blocks the interaction with and phosphorylation of FAK. Upon netrin-1 stimulation TRIM9 promotes DCC multimerization, but TRIM9-dependent ubiquitination of DCC is reduced, which promotes an interaction with FAK and subsequent FAK activation. We found that inhibition of FAK activity blocks elevated frequencies of exocytosis in vitro and elevated axon branching in vitro and in vivo. Although FAK inhibition decreased soluble N-ethylmaleimide attachment protein receptor (SNARE)-mediated exocytosis, assembled SNARE complexes and vesicles adjacent to the plasma membrane increased, suggesting a novel role for FAK in the progression from assembled SNARE complexes to vesicle fusion in developing murine neurons. The American Society for Cell Biology 2017-09-01 /pmc/articles/PMC5576901/ /pubmed/28701345 http://dx.doi.org/10.1091/mbc.E16-08-0594 Text en © 2017 Plooster, Menon, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Plooster, Melissa
Menon, Shalini
Winkle, Cortney C.
Urbina, Fabio L.
Monkiewicz, Caroline
Phend, Kristen D.
Weinberg, Richard J.
Gupton, Stephanie L.
TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching
title TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching
title_full TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching
title_fullStr TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching
title_full_unstemmed TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching
title_short TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching
title_sort trim9-dependent ubiquitination of dcc constrains kinase signaling, exocytosis, and axon branching
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576901/
https://www.ncbi.nlm.nih.gov/pubmed/28701345
http://dx.doi.org/10.1091/mbc.E16-08-0594
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