Generation of a chemical genetic model for JAK3
Abstract Janus Kinases (JAKs) have emerged as an important drug target for the treatment of a number of immune disorders due to the central role that they play in cytokine signalling. 4 isoforms of JAKs exist in mammalian cells and the ideal isoform profile of a JAK inhibitor has been the subject of...
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2021
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oai:doaj.org-article:66b7f58af7964f179690d105103789582021-12-02T15:43:17ZGeneration of a chemical genetic model for JAK310.1038/s41598-021-89356-42045-2322https://doaj.org/article/66b7f58af7964f179690d105103789582021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89356-4https://doaj.org/toc/2045-2322Abstract Janus Kinases (JAKs) have emerged as an important drug target for the treatment of a number of immune disorders due to the central role that they play in cytokine signalling. 4 isoforms of JAKs exist in mammalian cells and the ideal isoform profile of a JAK inhibitor has been the subject of much debate. JAK3 has been proposed as an ideal target due to its expression being largely restricted to the immune system and its requirement for signalling by cytokine receptors using the common γ-chain. Unlike other JAKs, JAK3 possesses a cysteine in its ATP binding pocket and this has allowed the design of isoform selective covalent JAK3 inhibitors targeting this residue. We report here that mutating this cysteine to serine does not prevent JAK3 catalytic activity but does greatly increase the IC50 for covalent JAK3 inhibitors. Mice with a Cys905Ser knockin mutation in the endogenous JAK3 gene are viable and show no apparent welfare issues. Cells from these mice show normal STAT phosphorylation in response to JAK3 dependent cytokines but are resistant to the effects of covalent JAK3 inhibitors. These mice therefore provide a chemical-genetic model to study JAK3 function.Judit RemenyiRangeetha Jayaprakash NaikJinhua WangMomchil RazsolkovAlyssa VeranoQuan CaiLi TanRachel TothSamantha RaggettCarla BaillieRyan TraynorC. James HastieNathanael S. GrayJ. Simon C. ArthurNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Judit Remenyi Rangeetha Jayaprakash Naik Jinhua Wang Momchil Razsolkov Alyssa Verano Quan Cai Li Tan Rachel Toth Samantha Raggett Carla Baillie Ryan Traynor C. James Hastie Nathanael S. Gray J. Simon C. Arthur Generation of a chemical genetic model for JAK3 |
| description |
Abstract Janus Kinases (JAKs) have emerged as an important drug target for the treatment of a number of immune disorders due to the central role that they play in cytokine signalling. 4 isoforms of JAKs exist in mammalian cells and the ideal isoform profile of a JAK inhibitor has been the subject of much debate. JAK3 has been proposed as an ideal target due to its expression being largely restricted to the immune system and its requirement for signalling by cytokine receptors using the common γ-chain. Unlike other JAKs, JAK3 possesses a cysteine in its ATP binding pocket and this has allowed the design of isoform selective covalent JAK3 inhibitors targeting this residue. We report here that mutating this cysteine to serine does not prevent JAK3 catalytic activity but does greatly increase the IC50 for covalent JAK3 inhibitors. Mice with a Cys905Ser knockin mutation in the endogenous JAK3 gene are viable and show no apparent welfare issues. Cells from these mice show normal STAT phosphorylation in response to JAK3 dependent cytokines but are resistant to the effects of covalent JAK3 inhibitors. These mice therefore provide a chemical-genetic model to study JAK3 function. |
| format |
article |
| author |
Judit Remenyi Rangeetha Jayaprakash Naik Jinhua Wang Momchil Razsolkov Alyssa Verano Quan Cai Li Tan Rachel Toth Samantha Raggett Carla Baillie Ryan Traynor C. James Hastie Nathanael S. Gray J. Simon C. Arthur |
| author_facet |
Judit Remenyi Rangeetha Jayaprakash Naik Jinhua Wang Momchil Razsolkov Alyssa Verano Quan Cai Li Tan Rachel Toth Samantha Raggett Carla Baillie Ryan Traynor C. James Hastie Nathanael S. Gray J. Simon C. Arthur |
| author_sort |
Judit Remenyi |
| title |
Generation of a chemical genetic model for JAK3 |
| title_short |
Generation of a chemical genetic model for JAK3 |
| title_full |
Generation of a chemical genetic model for JAK3 |
| title_fullStr |
Generation of a chemical genetic model for JAK3 |
| title_full_unstemmed |
Generation of a chemical genetic model for JAK3 |
| title_sort |
generation of a chemical genetic model for jak3 |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/66b7f58af7964f179690d10510378958 |
| work_keys_str_mv |
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| _version_ |
1718385810791727104 |