Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket.
The stem cell factor receptor (SCF) c-Kit plays a pivotal role in regulating cell proliferation and survival in many cell types. In particular, c-Kit is required for early amplification of erythroid progenitors, while it must disappear from cell surface for the cell entering the final steps of matur...
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2013
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oai:doaj.org-article:fa067dc590e84f4ea8744597e596650e2021-11-18T07:48:10ZTyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket.1932-620310.1371/journal.pone.0060961https://doaj.org/article/fa067dc590e84f4ea8744597e596650e2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23637779/?tool=EBIhttps://doaj.org/toc/1932-6203The stem cell factor receptor (SCF) c-Kit plays a pivotal role in regulating cell proliferation and survival in many cell types. In particular, c-Kit is required for early amplification of erythroid progenitors, while it must disappear from cell surface for the cell entering the final steps of maturation in an erythropoietin-dependent manner. We initially observed that imatinib (IM), an inhibitor targeting the tyrosine kinase activity of c-Kit concomitantly down-regulated the expression of c-Kit and accelerated the Epo-driven differentiation of erythroblasts in the absence of SCF. We investigated the mechanism by which IM or related masitinib (MA) induce c-Kit down-regulation in the human UT-7/Epo cell line. We found that the down-regulation of c-Kit in the presence of IM or MA was inhibited by a pre-incubation with methyl-β-cyclodextrin suggesting that c-Kit was internalized in the absence of ligand. By contrast to SCF, the internalization induced by TKI was independent of the E3 ubiquitin ligase c-Cbl. Furthermore, c-Kit was degraded through lysosomal, but not proteasomal pathway. In pulse-chase experiments, IM did not modulate c-Kit synthesis or maturation. Analysis of phosphotyrosine peptides in UT-7/Epo cells treated or not with IM show that IM did not modify overall tyrosine phosphorylation in these cells. Furthermore, we showed that a T670I mutation preventing the full access of IM to the ATP binding pocket, did not allow the internalization process in the presence of IM. Altogether these data show that TKI-induced internalization of c-Kit is linked to a modification of the integrity of ATP binding pocket.Diane D'allardJulie GayClotilde DescarpentriesEmilie FrisanKevin AdamFrederique VerdierCélia FloquetPatrice DubreuilCatherine LacombeMichaela FontenayPatrick MayeuxOlivier KosmiderPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e60961 (2013) |
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Medicine R Science Q Diane D'allard Julie Gay Clotilde Descarpentries Emilie Frisan Kevin Adam Frederique Verdier Célia Floquet Patrice Dubreuil Catherine Lacombe Michaela Fontenay Patrick Mayeux Olivier Kosmider Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. |
| description |
The stem cell factor receptor (SCF) c-Kit plays a pivotal role in regulating cell proliferation and survival in many cell types. In particular, c-Kit is required for early amplification of erythroid progenitors, while it must disappear from cell surface for the cell entering the final steps of maturation in an erythropoietin-dependent manner. We initially observed that imatinib (IM), an inhibitor targeting the tyrosine kinase activity of c-Kit concomitantly down-regulated the expression of c-Kit and accelerated the Epo-driven differentiation of erythroblasts in the absence of SCF. We investigated the mechanism by which IM or related masitinib (MA) induce c-Kit down-regulation in the human UT-7/Epo cell line. We found that the down-regulation of c-Kit in the presence of IM or MA was inhibited by a pre-incubation with methyl-β-cyclodextrin suggesting that c-Kit was internalized in the absence of ligand. By contrast to SCF, the internalization induced by TKI was independent of the E3 ubiquitin ligase c-Cbl. Furthermore, c-Kit was degraded through lysosomal, but not proteasomal pathway. In pulse-chase experiments, IM did not modulate c-Kit synthesis or maturation. Analysis of phosphotyrosine peptides in UT-7/Epo cells treated or not with IM show that IM did not modify overall tyrosine phosphorylation in these cells. Furthermore, we showed that a T670I mutation preventing the full access of IM to the ATP binding pocket, did not allow the internalization process in the presence of IM. Altogether these data show that TKI-induced internalization of c-Kit is linked to a modification of the integrity of ATP binding pocket. |
| format |
article |
| author |
Diane D'allard Julie Gay Clotilde Descarpentries Emilie Frisan Kevin Adam Frederique Verdier Célia Floquet Patrice Dubreuil Catherine Lacombe Michaela Fontenay Patrick Mayeux Olivier Kosmider |
| author_facet |
Diane D'allard Julie Gay Clotilde Descarpentries Emilie Frisan Kevin Adam Frederique Verdier Célia Floquet Patrice Dubreuil Catherine Lacombe Michaela Fontenay Patrick Mayeux Olivier Kosmider |
| author_sort |
Diane D'allard |
| title |
Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. |
| title_short |
Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. |
| title_full |
Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. |
| title_fullStr |
Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. |
| title_full_unstemmed |
Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. |
| title_sort |
tyrosine kinase inhibitors induce down-regulation of c-kit by targeting the atp pocket. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/fa067dc590e84f4ea8744597e596650e |
| work_keys_str_mv |
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| _version_ |
1718422950258933760 |