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Alternative splicing results in RET isoforms with distinct trafficking properties

RET encodes a receptor tyrosine kinase that is essential for spermatogenesis, development of the sensory, sympathetic, parasympathetic, and enteric nervous systems and the kidneys, as well as for maintenance of adult midbrain dopaminergic neurons. RET is alternatively spliced to encode multiple isof...

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Autores principales: Richardson, Douglas S., Rodrigues, David M., Hyndman, Brandy D., Crupi, Mathieu J. F., Nicolescu, Adrian C., Mulligan, Lois M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459860/
https://www.ncbi.nlm.nih.gov/pubmed/22875993
http://dx.doi.org/10.1091/mbc.E12-02-0114
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author Richardson, Douglas S.
Rodrigues, David M.
Hyndman, Brandy D.
Crupi, Mathieu J. F.
Nicolescu, Adrian C.
Mulligan, Lois M.
author_facet Richardson, Douglas S.
Rodrigues, David M.
Hyndman, Brandy D.
Crupi, Mathieu J. F.
Nicolescu, Adrian C.
Mulligan, Lois M.
author_sort Richardson, Douglas S.
collection PubMed
description RET encodes a receptor tyrosine kinase that is essential for spermatogenesis, development of the sensory, sympathetic, parasympathetic, and enteric nervous systems and the kidneys, as well as for maintenance of adult midbrain dopaminergic neurons. RET is alternatively spliced to encode multiple isoforms that differ in their C-terminal amino acids. The RET9 and RET51 isoforms display unique levels of autophosphorylation and have differential interactions with adaptor proteins. They induce distinct gene expression patterns, promote different levels of cell differentiation and transformation, and play unique roles in development. Here we present a comprehensive study of the subcellular localization and trafficking of RET isoforms. We show that immature RET9 accumulates intracellularly in the Golgi, whereas RET51 is efficiently matured and present in relatively higher amounts on the plasma membrane. RET51 is internalized faster after ligand binding and undergoes recycling back to the plasma membrane. This differential trafficking of RET isoforms produces a more rapid and longer duration of signaling through the extracellular-signal regulated kinase/mitogen-activated protein kinase pathway downstream of RET51 relative to RET9. Together these differences in trafficking properties contribute to some of the functional differences previously observed between RET9 and RET51 and establish the important role of intracellular trafficking in modulating and maintaining RET signaling.
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spelling pubmed-34598602012-12-16 Alternative splicing results in RET isoforms with distinct trafficking properties Richardson, Douglas S. Rodrigues, David M. Hyndman, Brandy D. Crupi, Mathieu J. F. Nicolescu, Adrian C. Mulligan, Lois M. Mol Biol Cell Articles RET encodes a receptor tyrosine kinase that is essential for spermatogenesis, development of the sensory, sympathetic, parasympathetic, and enteric nervous systems and the kidneys, as well as for maintenance of adult midbrain dopaminergic neurons. RET is alternatively spliced to encode multiple isoforms that differ in their C-terminal amino acids. The RET9 and RET51 isoforms display unique levels of autophosphorylation and have differential interactions with adaptor proteins. They induce distinct gene expression patterns, promote different levels of cell differentiation and transformation, and play unique roles in development. Here we present a comprehensive study of the subcellular localization and trafficking of RET isoforms. We show that immature RET9 accumulates intracellularly in the Golgi, whereas RET51 is efficiently matured and present in relatively higher amounts on the plasma membrane. RET51 is internalized faster after ligand binding and undergoes recycling back to the plasma membrane. This differential trafficking of RET isoforms produces a more rapid and longer duration of signaling through the extracellular-signal regulated kinase/mitogen-activated protein kinase pathway downstream of RET51 relative to RET9. Together these differences in trafficking properties contribute to some of the functional differences previously observed between RET9 and RET51 and establish the important role of intracellular trafficking in modulating and maintaining RET signaling. The American Society for Cell Biology 2012-10-01 /pmc/articles/PMC3459860/ /pubmed/22875993 http://dx.doi.org/10.1091/mbc.E12-02-0114 Text en © 2012 Richardson 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 of Cell BD; are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Richardson, Douglas S.
Rodrigues, David M.
Hyndman, Brandy D.
Crupi, Mathieu J. F.
Nicolescu, Adrian C.
Mulligan, Lois M.
Alternative splicing results in RET isoforms with distinct trafficking properties
title Alternative splicing results in RET isoforms with distinct trafficking properties
title_full Alternative splicing results in RET isoforms with distinct trafficking properties
title_fullStr Alternative splicing results in RET isoforms with distinct trafficking properties
title_full_unstemmed Alternative splicing results in RET isoforms with distinct trafficking properties
title_short Alternative splicing results in RET isoforms with distinct trafficking properties
title_sort alternative splicing results in ret isoforms with distinct trafficking properties
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459860/
https://www.ncbi.nlm.nih.gov/pubmed/22875993
http://dx.doi.org/10.1091/mbc.E12-02-0114
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