The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction.
(2009) In Journal of Biological Chemistry 284(17). p.11039-11047- Abstract
- The receptor tyrosine kinase c-Kit plays a critical role in hematopoiesis and gain-of-function mutations of the receptor are frequently seen in several malignancies, including acute myeloid leukemia (AML), gastrointestinal stromal tumors and testicular carcinoma. The most common mutation of c-Kit in these disorders is a substitution of the aspartic acid residue in position 816 to a valine (D816V), leading to constitutive activation of the receptor. In this study we aimed to investigate the role of Src family kinases in c-Kit/D816V signaling. Src family kinases are necessary for the phosphorylation of wild-type c-Kit as well as of activation of downstream signaling pathways including receptor ubiquitination and the Ras/Mek/Erk pathway. Our... (More)
- The receptor tyrosine kinase c-Kit plays a critical role in hematopoiesis and gain-of-function mutations of the receptor are frequently seen in several malignancies, including acute myeloid leukemia (AML), gastrointestinal stromal tumors and testicular carcinoma. The most common mutation of c-Kit in these disorders is a substitution of the aspartic acid residue in position 816 to a valine (D816V), leading to constitutive activation of the receptor. In this study we aimed to investigate the role of Src family kinases in c-Kit/D816V signaling. Src family kinases are necessary for the phosphorylation of wild-type c-Kit as well as of activation of downstream signaling pathways including receptor ubiquitination and the Ras/Mek/Erk pathway. Our data demonstrate that, unlike wild-type c-Kit, the phosphorylation of c-Kit/D816V is not dependent on Src family kinases. In addition we found that neither receptor ubiquitination nor Erk activation by c-Kit/D816V required activation of Src family kinases. In vitro kinase assay using synthetic peptides revealed that c-Kit/D816V had an altered substrate specificity resembling Src and Abl tyrosine kinases. We further present evidence that, in contrast to wild-type c-Kit, Src family kinases are dispensable for c-Kit/D816V cell survival, proliferation and colony formation. Taken together, we demonstrate that the signal transduction pathways mediated by c-Kit/D816V are markedly different from those activated by wild-type c-Kit and that altered substrate specificity of c-Kit circumvents a need for Src family kinases in signaling of growth and survival, thereby contributing to the transforming potential of c-Kit/D816V. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1367984
- author
- Sun, Jianmin LU ; Pedersen, Malin LU and Rönnstrand, Lars LU
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 284
- issue
- 17
- pages
- 11039 - 11047
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000265494500008
- pmid:19265199
- scopus:66449128486
- pmid:19265199
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M808058200
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
- id
- d6347800-40de-4be1-a33a-69cd03bc27cd (old id 1367984)
- date added to LUP
- 2016-04-01 12:31:19
- date last changed
- 2022-04-13 20:06:12
@article{d6347800-40de-4be1-a33a-69cd03bc27cd, abstract = {{The receptor tyrosine kinase c-Kit plays a critical role in hematopoiesis and gain-of-function mutations of the receptor are frequently seen in several malignancies, including acute myeloid leukemia (AML), gastrointestinal stromal tumors and testicular carcinoma. The most common mutation of c-Kit in these disorders is a substitution of the aspartic acid residue in position 816 to a valine (D816V), leading to constitutive activation of the receptor. In this study we aimed to investigate the role of Src family kinases in c-Kit/D816V signaling. Src family kinases are necessary for the phosphorylation of wild-type c-Kit as well as of activation of downstream signaling pathways including receptor ubiquitination and the Ras/Mek/Erk pathway. Our data demonstrate that, unlike wild-type c-Kit, the phosphorylation of c-Kit/D816V is not dependent on Src family kinases. In addition we found that neither receptor ubiquitination nor Erk activation by c-Kit/D816V required activation of Src family kinases. In vitro kinase assay using synthetic peptides revealed that c-Kit/D816V had an altered substrate specificity resembling Src and Abl tyrosine kinases. We further present evidence that, in contrast to wild-type c-Kit, Src family kinases are dispensable for c-Kit/D816V cell survival, proliferation and colony formation. Taken together, we demonstrate that the signal transduction pathways mediated by c-Kit/D816V are markedly different from those activated by wild-type c-Kit and that altered substrate specificity of c-Kit circumvents a need for Src family kinases in signaling of growth and survival, thereby contributing to the transforming potential of c-Kit/D816V.}}, author = {{Sun, Jianmin and Pedersen, Malin and Rönnstrand, Lars}}, issn = {{1083-351X}}, language = {{eng}}, number = {{17}}, pages = {{11039--11047}}, publisher = {{American Society for Biochemistry and Molecular Biology}}, series = {{Journal of Biological Chemistry}}, title = {{The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction.}}, url = {{https://lup.lub.lu.se/search/files/2957073/1390669.pdf}}, doi = {{10.1074/jbc.M808058200}}, volume = {{284}}, year = {{2009}}, }