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NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner
NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tum...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927325/ https://www.ncbi.nlm.nih.gov/pubmed/30726988 http://dx.doi.org/10.1093/jmcb/mjz003 |
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author | Wei, Ran Liu, Xuguang Voss, Courtney Qin, Wentao Dagnino, Lina Li, Lei Vigny, Marc Li, Shawn Shun-Cheng |
author_facet | Wei, Ran Liu, Xuguang Voss, Courtney Qin, Wentao Dagnino, Lina Li, Lei Vigny, Marc Li, Shawn Shun-Cheng |
author_sort | Wei, Ran |
collection | PubMed |
description | NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation. |
format | Online Article Text |
id | pubmed-6927325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-69273252019-12-27 NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner Wei, Ran Liu, Xuguang Voss, Courtney Qin, Wentao Dagnino, Lina Li, Lei Vigny, Marc Li, Shawn Shun-Cheng J Mol Cell Biol Original Article NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation. Oxford University Press 2019-02-06 /pmc/articles/PMC6927325/ /pubmed/30726988 http://dx.doi.org/10.1093/jmcb/mjz003 Text en © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Wei, Ran Liu, Xuguang Voss, Courtney Qin, Wentao Dagnino, Lina Li, Lei Vigny, Marc Li, Shawn Shun-Cheng NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
title | NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
title_full | NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
title_fullStr | NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
title_full_unstemmed | NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
title_short | NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
title_sort | numb regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927325/ https://www.ncbi.nlm.nih.gov/pubmed/30726988 http://dx.doi.org/10.1093/jmcb/mjz003 |
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