دورية أكاديمية
أعرض في EDS

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis.

التفاصيل البيبلوغرافية
العنوان: Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis.
المؤلفون: Tabata J; Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan., Nakaoku T; Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan., Araki M; Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yoshino R; Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan., Kohsaka S; Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan., Otsuka A; Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan., Ikegami M; Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan., Ui A; Department of Molecular Oncology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan., Kanno SI; Department of Molecular Oncology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan., Miyoshi K; Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan., Matsumoto S; Graduate School of Medicine, Kyoto University, Kyoto, Japan., Sagae Y; Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yasui A; IDAC Fellow Laboratory, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan., Sekijima M; Department of Computer Science, Tokyo Institute of Technology, Yokohama, Japan., Mano H; Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan., Okuno Y; Graduate School of Medicine, Kyoto University, Kyoto, Japan., Okamoto A; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan., Kohno T; Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
المصدر: Cancer research [Cancer Res] 2022 Oct 17; Vol. 82 (20), pp. 3751-3762.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
مواضيع طبية MeSH: Drosophila Proteins*/genetics , Multiple Endocrine Neoplasia Type 2a*/genetics , Multiple Endocrine Neoplasia Type 2a*/metabolism , Neoplasms*/genetics, Calcium/metabolism ; Calmodulin/genetics ; Calmodulin/metabolism ; Carcinogenesis/genetics ; Cysteine/genetics ; Cysteine/metabolism ; Disulfides/metabolism ; Humans ; Ligands ; Mutation ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-ret/genetics
مستخلص: Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico-driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations.
Significance: Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.
(©2022 The Authors; Published by the American Association for Cancer Research.)
References: Nat Rev Cancer. 2021 Sep;21(9):579-591. (PMID: 34188192)
JCO Precis Oncol. 2020 Apr 14;4:. (PMID: 32923911)
JCO Precis Oncol. 2017 Jul;2017:. (PMID: 28890946)
Lancet Diabetes Endocrinol. 2021 Aug;9(8):491-501. (PMID: 34118198)
Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
Bioinformatics. 2019 Nov 1;35(22):4788-4790. (PMID: 31228182)
Carcinogenesis. 2020 Apr 22;41(2):123-129. (PMID: 31711124)
Trends Cancer. 2021 Dec;7(12):1074-1088. (PMID: 34391699)
N Engl J Med. 2020 Aug 27;383(9):813-824. (PMID: 32846060)
Nat Struct Mol Biol. 2022 Jan;29(1):1-2. (PMID: 35046575)
Cancer Cell. 2014 Sep 8;26(3):428-442. (PMID: 25132497)
Cell Syst. 2018 Mar 28;6(3):271-281.e7. (PMID: 29596782)
Sci Transl Med. 2017 Nov 15;9(416):. (PMID: 29141884)
Nat Commun. 2018 Feb 12;9(1):625. (PMID: 29434222)
J Comput Chem. 1999 Jun;20(8):786-798. (PMID: 35619462)
Mol Cell. 2014 Mar 6;53(5):738-51. (PMID: 24560924)
N Engl J Med. 2020 Aug 13;383(7):640-649. (PMID: 32786189)
Cancer Discov. 2017 Aug;7(8):818-831. (PMID: 28572459)
N Engl J Med. 2021 Jun 24;384(25):2371-2381. (PMID: 34096690)
Nat Rev Cancer. 2014 Mar;14(3):173-86. (PMID: 24561444)
Nat Rev Endocrinol. 2016 Apr;12(4):192-202. (PMID: 26868437)
N Engl J Med. 2010 Jun 24;362(25):2380-8. (PMID: 20573926)
EBioMedicine. 2015 Jan;2(1):74-81. (PMID: 26023681)
J Clin Oncol. 2020 Apr 10;38(11):1209-1221. (PMID: 32083997)
Cancer Cell. 2019 Oct 14;36(4):431-443.e5. (PMID: 31543464)
Clin Lung Cancer. 2022 Jan;23(1):e5-e8. (PMID: 34246540)
Elife. 2019 Sep 19;8:. (PMID: 31535977)
J Chem Theory Comput. 2019 Mar 12;15(3):1863-1874. (PMID: 30768902)
N Engl J Med. 2011 Jun 30;364(26):2507-16. (PMID: 21639808)
ACS Chem Biol. 2016 Feb 19;11(2):400-8. (PMID: 26569370)
Proc Natl Acad Sci U S A. 2019 May 14;116(20):10025-10030. (PMID: 31043566)
NPJ Precis Oncol. 2021 Apr 16;5(1):32. (PMID: 33863983)
J Chem Theory Comput. 2016 Apr 12;12(4):1845-52. (PMID: 26949976)
J Comput Chem. 2021 Feb 5;42(4):231-241. (PMID: 33200457)
J Mol Biol. 2002 Jul 12;320(3):597-608. (PMID: 12096912)
JCO Precis Oncol. 2021 Jan 11;5:. (PMID: 34036231)
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10556-E10565. (PMID: 30348784)
Sci Adv. 2019 Jul 31;5(7):eaau4202. (PMID: 31392261)
Clin Cancer Res. 2019 Oct 1;25(19):5832-5842. (PMID: 31300450)
J Cell Biochem. 2019 Aug;120(8):13046-13055. (PMID: 30916819)
Acc Chem Res. 2000 Dec;33(12):889-97. (PMID: 11123888)
Nat Med. 2012 Feb 12;18(3):375-7. (PMID: 22327624)
Circulation. 2002 Jul 2;106(1):69-74. (PMID: 12093772)
J Chem Phys. 2007 Jan 7;126(1):014101. (PMID: 17212484)
N Engl J Med. 2020 Aug 27;383(9):825-835. (PMID: 32846061)
Proteins. 2004 May 1;55(2):351-67. (PMID: 15048827)
Lancet Oncol. 2021 Jul;22(7):959-969. (PMID: 34118197)
Proteins. 2005 Dec 1;61(4):704-21. (PMID: 16231289)
Proteins. 2010 Jun;78(8):1950-8. (PMID: 20408171)
المشرفين على المادة: 0 (Calmodulin)
0 (Disulfides)
0 (Drosophila Proteins)
0 (Ligands)
0 (Protein Kinase Inhibitors)
0 (Proto-Oncogene Proteins)
EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
EC 2.7.10.1 (RET protein, human)
K848JZ4886 (Cysteine)
SY7Q814VUP (Calcium)
تواريخ الأحداث: Date Created: 20220927 Date Completed: 20221018 Latest Revision: 20230106
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9574375
DOI: 10.1158/0008-5472.CAN-22-0834
PMID: 36166639
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-7445
DOI:10.1158/0008-5472.CAN-22-0834