Cargando…
SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation
KIT is a receptor tyrosine kinase (RTK) involved in several cellular processes such as regulation of proliferation, survival and differentiation of early hematopoietic cells, germ cells and melanocytes. Activation of KIT results in phosphorylation of tyrosine residues in the receptor, and recruitmen...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913247/ https://www.ncbi.nlm.nih.gov/pubmed/29686302 http://dx.doi.org/10.1038/s41598-018-24743-y |
_version_ | 1783316499786629120 |
---|---|
author | Rupar, Kaja Moharram, Sausan A. Kazi, Julhash U. Rönnstrand, Lars |
author_facet | Rupar, Kaja Moharram, Sausan A. Kazi, Julhash U. Rönnstrand, Lars |
author_sort | Rupar, Kaja |
collection | PubMed |
description | KIT is a receptor tyrosine kinase (RTK) involved in several cellular processes such as regulation of proliferation, survival and differentiation of early hematopoietic cells, germ cells and melanocytes. Activation of KIT results in phosphorylation of tyrosine residues in the receptor, and recruitment of proteins that mediate downstream signaling and also modulate receptor signaling. Here we show that the SRC-like adaptor protein 2 (SLAP2) binds to wild-type KIT in a ligand-dependent manner and is furthermore found constitutively associated with the oncogenic mutant KIT-D816V. Peptide fishing analysis mapped pY568 and pY570 as potential SLAP2 association sites in KIT, which overlaps with the SRC binding sites in KIT. Expression of SLAP2 in cells expressing the transforming mutant KIT-D816V led to reduced cell viability and reduced colony formation. SLAP2 also partially blocked phosphorylation of several signal transduction molecules downstream of KIT such as AKT, ERK, p38 and STAT3. Finally, SLAP2 expression enhanced ubiquitination of KIT and its subsequent degradation. Taken together, our data demonstrate that SLAP2 negatively modulates KIT-D816V-mediated transformation by enhancing degradation of the receptor. |
format | Online Article Text |
id | pubmed-5913247 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59132472018-04-30 SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation Rupar, Kaja Moharram, Sausan A. Kazi, Julhash U. Rönnstrand, Lars Sci Rep Article KIT is a receptor tyrosine kinase (RTK) involved in several cellular processes such as regulation of proliferation, survival and differentiation of early hematopoietic cells, germ cells and melanocytes. Activation of KIT results in phosphorylation of tyrosine residues in the receptor, and recruitment of proteins that mediate downstream signaling and also modulate receptor signaling. Here we show that the SRC-like adaptor protein 2 (SLAP2) binds to wild-type KIT in a ligand-dependent manner and is furthermore found constitutively associated with the oncogenic mutant KIT-D816V. Peptide fishing analysis mapped pY568 and pY570 as potential SLAP2 association sites in KIT, which overlaps with the SRC binding sites in KIT. Expression of SLAP2 in cells expressing the transforming mutant KIT-D816V led to reduced cell viability and reduced colony formation. SLAP2 also partially blocked phosphorylation of several signal transduction molecules downstream of KIT such as AKT, ERK, p38 and STAT3. Finally, SLAP2 expression enhanced ubiquitination of KIT and its subsequent degradation. Taken together, our data demonstrate that SLAP2 negatively modulates KIT-D816V-mediated transformation by enhancing degradation of the receptor. Nature Publishing Group UK 2018-04-23 /pmc/articles/PMC5913247/ /pubmed/29686302 http://dx.doi.org/10.1038/s41598-018-24743-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rupar, Kaja Moharram, Sausan A. Kazi, Julhash U. Rönnstrand, Lars SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation |
title | SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation |
title_full | SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation |
title_fullStr | SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation |
title_full_unstemmed | SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation |
title_short | SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation |
title_sort | src-like adaptor protein 2 (slap2) is a negative regulator of kit-d816v-mediated oncogenic transformation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913247/ https://www.ncbi.nlm.nih.gov/pubmed/29686302 http://dx.doi.org/10.1038/s41598-018-24743-y |
work_keys_str_mv | AT ruparkaja srclikeadaptorprotein2slap2isanegativeregulatorofkitd816vmediatedoncogenictransformation AT moharramsausana srclikeadaptorprotein2slap2isanegativeregulatorofkitd816vmediatedoncogenictransformation AT kazijulhashu srclikeadaptorprotein2slap2isanegativeregulatorofkitd816vmediatedoncogenictransformation AT ronnstrandlars srclikeadaptorprotein2slap2isanegativeregulatorofkitd816vmediatedoncogenictransformation |