Clustered cysteine residues in the kinase domain of v-Src: critical role for protein stability, cell transformation and sensitivity to herbimycin A

Senga, Takeshi; Miyazaki, Koichi; Machida, Kazuya; Iwata, Hiroyuki; Matsuda, Satoru; Nakashima, Izumi; Hamaguchi, Michinari

doi:10.1038/sj.onc.1203296

Cited by 48 publications

(44 citation statements)

References 34 publications

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“…They showed that the inactivation was caused by oxidation of Cys 277 , which resulted in homodimerization of c-Src linked by a disulfide bridge. We previously reported the critical role of cysteine residues in the CC motif for the regulation of catalytic activity of c-Src (18). SH-alkylating agents such as BIPM and NAM are known to inhibit kinase activity of v-Src by directly binding to cysteine residues.…”

Section: Discussionmentioning

confidence: 99%

“…Substitution of amino acids was performed as described previously (18), and each mutation was confirmed by sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the phosphorylation-based regulation of c-Src, recent studies have indicated a possible role of cysteine modification for the regulation of the kinase (16,17). Our previous studies have indicated the importance of cysteine residues located in the C terminus of the catalytic domain (18,19). Four cysteines, namely Cys 483 , Cys 487 , Cys 496 , and Cys 498 are clustered in the C terminus of c-Src, which we referred to as the cysteine-clustered motif (CC motif) (20).…”

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confidence: 99%

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S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

Rahman

Senga

Ito

et al. 2010

Journal of Biological Chemistry

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101

107

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Section: Discussionmentioning

confidence: 99%

“…Substitution of amino acids was performed as described previously (18), and each mutation was confirmed by sequencing.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

Rahman

Senga

Ito

et al. 2010

Journal of Biological Chemistry

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101

107

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“…Interestingly, cysteine 376 of Ret-PTC-1 or its equivalent is most highly conserved in the sequences of various tyrosine kinases, including Ros, Abl, Src, Fms, Fps, HIR, HER, and Lck (Takahashi et al, 1987), suggesting its critical role in the maintenance and up-regulation of the basal level of catalytic activity of Ret and potentially other tyrosine kinases. Correspondingly, cysteine 475 of Lck (Veillette et al, 1993) and cysteine 498 of v-Src (Senga et al, 2000), equivalents of cysteine 376 of Ret-PTC-1, have been shown to be crucial for either catalytic activity or transforming activity of the kinase.…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Kato¹,

Iwashita

Takeda³

et al. 2000

MBoC

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The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its mutations in the germ line are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%) and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30 -40%) were dimerized through disulfide bonds. These dimerized Ret proteins were preferentially autophosphorylated, suggesting a close relation between up-regulated kinase activity and disulfide bond-mediated dimerization of Ret proteins. We found that UV irradiation promotes the disulfide bond-mediated dimerization of the Ret proteins, in close association with activation and superactivation of Ret kinases. UV irradiation also induced dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and were not increased by UV irradiation. These results suggest that Ret-PTC-1 cysteine 376 is one of possibly multiple critical target amino acids of UV for Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a result of gene transfection prevented both the UVmediated promotion of dimerization and the superactivation of Ret-MEN2A kinase. These results suggest that the UV-induced free radicals in cells attack intracellular domains of Ret to dimerize the kinase proteins for superactivation.

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“…Subsequent studies by Senga et al (2000) identified a number of cysteine residues in Src necessary for the enzymes stability and transformative ability. Giannoni et al (2005) focused on Cys245 and Cys487 which were demonstrated to undergo intramolecular Although these studies support a model whereby Src is activated in response to ROS, data consistent with an inhibitory role for ROS in Src activity has also been proffered by Kemble et al (2009).…”

Section: Discussionmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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Clustered cysteine residues in the kinase domain of v-Src: critical role for protein stability, cell transformation and sensitivity to herbimycin A

Cited by 48 publications

References 34 publications

S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

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