Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis

AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions...

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Autores principales:	Vivian Lee, Thomas D Griffin, Yoko Suzuki-Horiuchi, Lily Wushanley, Yerin Kweon, Christine Marshall, Weijie Li, Elias Ayli, Adele Haimovic, Aliya Hines, John T Seykora
Formato:	article
Lenguaje:	EN
Publicado:	Wolters Kluwer Medknow Publications 2021
Materias:	cancer cbl srcasm src-family kinases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b34910f78a404e85b88aefde8e2d87af
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spelling	oai:doaj.org-article:b34910f78a404e85b88aefde8e2d87af2021-11-12T10:17:20ZDownregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis1477-316310.4103/jcar.jcar_13_21https://doaj.org/article/b34910f78a404e85b88aefde8e2d87af2021-01-01T00:00:00Zhttp://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2021;volume=20;issue=1;spage=21;epage=21;aulast=Leehttps://doaj.org/toc/1477-3163AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs.MATERIALS AND METHODS: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition.RESULTS: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism.CONCLUSION: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.Vivian LeeThomas D GriffinYoko Suzuki-HoriuchiLily WushanleyYerin KweonChristine MarshallWeijie LiElias AyliAdele HaimovicAliya HinesJohn T SeykoraWolters Kluwer Medknow Publicationsarticlecancercblsrcasmsrc-family kinasesNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Carcinogenesis, Vol 20, Iss 1, Pp 21-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer cbl srcasm src-family kinases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cancer cbl srcasm src-family kinases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Vivian Lee Thomas D Griffin Yoko Suzuki-Horiuchi Lily Wushanley Yerin Kweon Christine Marshall Weijie Li Elias Ayli Adele Haimovic Aliya Hines John T Seykora Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis
description	AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs.MATERIALS AND METHODS: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition.RESULTS: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism.CONCLUSION: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.
format	article
author	Vivian Lee Thomas D Griffin Yoko Suzuki-Horiuchi Lily Wushanley Yerin Kweon Christine Marshall Weijie Li Elias Ayli Adele Haimovic Aliya Hines John T Seykora
author_facet	Vivian Lee Thomas D Griffin Yoko Suzuki-Horiuchi Lily Wushanley Yerin Kweon Christine Marshall Weijie Li Elias Ayli Adele Haimovic Aliya Hines John T Seykora
author_sort	Vivian Lee
title	Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis
title_short	Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis
title_full	Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis
title_fullStr	Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis
title_full_unstemmed	Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis
title_sort	downregulation of src-family tyrosine kinases by srcasm and c-cbl: a comparative analysis
publisher	Wolters Kluwer Medknow Publications
publishDate	2021
url	https://doaj.org/article/b34910f78a404e85b88aefde8e2d87af
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Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis

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