Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer.
Animals
Antigens, CD19
/ metabolism
Autoimmunity
B-Lymphocytes
Calcium
/ metabolism
Cell Differentiation
Cell Transformation, Neoplastic
Enzyme Activation
Humans
Immune Tolerance
Lymphoma, B-Cell
/ enzymology
Mice
Models, Genetic
NFATC Transcription Factors
/ metabolism
Neoplasm Proteins
Neoplasms
/ enzymology
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Binding
Receptors, Antigen, B-Cell
/ metabolism
Signal Transduction
Syk Kinase
/ metabolism
ZAP-70 Protein-Tyrosine Kinase
/ metabolism
Anergy
B cell selection
Kinases
Leukemia
NFAT
Tolerance
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
20 05 2021
20 05 2021
Historique:
received:
11
06
2020
revised:
01
12
2020
accepted:
26
03
2021
pubmed:
21
4
2021
medline:
17
6
2021
entrez:
20
4
2021
Statut:
ppublish
Résumé
Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.
Identifiants
pubmed: 33878293
pii: S1097-2765(21)00264-1
doi: 10.1016/j.molcel.2021.03.043
pmc: PMC8239336
mid: NIHMS1692649
pii:
doi:
Substances chimiques
Antigens, CD19
0
NFATC Transcription Factors
0
Neoplasm Proteins
0
Receptors, Antigen, B-Cell
0
Syk Kinase
EC 2.7.10.2
ZAP-70 Protein-Tyrosine Kinase
EC 2.7.10.2
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2094-2111.e9Subventions
Organisme : NCI NIH HHS
ID : R01 CA240910
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213138
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118855
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA157644
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA233412
Pays : United States
Organisme : Howard Hughes Medical Institute
ID : 55108547
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197628
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI061093
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests E.M. is an advisor for and receives funding from AbbVie, Inc. All other authors declare no competing interests.
Références
Am J Clin Pathol. 2004 Oct;122(4):582-7
pubmed: 15487457
Nature. 1990 Mar 15;344(6263):251-3
pubmed: 2179728
J Pathol. 2005 Mar;205(4):507-13
pubmed: 15685592
Immunol Today. 1994 Sep;15(9):437-42
pubmed: 7524521
J Exp Med. 2016 Feb 8;213(2):155-65
pubmed: 26783323
Immunol Rev. 2010 Sep;237(1):249-63
pubmed: 20727040
Nat Immunol. 2012 Apr 18;13(5):439-47
pubmed: 22513334
Nature. 2012 Sep 13;489(7415):309-12
pubmed: 22885698
Cell. 2007 Oct 5;131(1):146-59
pubmed: 17923094
Nature. 1995 Aug 3;376(6539):435-8
pubmed: 7630421
Nature. 1997 Apr 24;386(6627):855-8
pubmed: 9126747
Eur J Immunol. 2017 Jun;47(6):932-945
pubmed: 28480512
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6955-60
pubmed: 12011454
Cold Spring Harb Perspect Biol. 2012 Apr 01;4(4):a007146
pubmed: 22378602
Nature. 2003 May 22;423(6938):452-6
pubmed: 12761551
Sci Immunol. 2016;1(1):
pubmed: 27917411
Clin Cancer Res. 2017 Sep 1;23(17):5292-5301
pubmed: 28536306
Blood. 2007 May 15;109(10):4424-31
pubmed: 17255355
Nat Immunol. 2008 Apr;9(4):405-14
pubmed: 18327259
Nat Med. 2016 Apr;22(4):379-87
pubmed: 26974310
J Proteome Res. 2018 Feb 2;17(2):759-769
pubmed: 29249144
J Clin Invest. 2018 Jan 2;128(1):415-426
pubmed: 29202478
EMBO J. 2018 Jun 1;37(11):
pubmed: 29669863
J Exp Med. 2003 Jul 7;198(1):91-8
pubmed: 12835482
Immunity. 2000 Jul;13(1):47-57
pubmed: 10933394
Immunol Today. 2000 Mar;21(3):148-54
pubmed: 10689303
Trends Cell Biol. 2006 Aug;16(8):388-90
pubmed: 16815013
PLoS One. 2012;7(4):e35497
pubmed: 22558161
Leukemia. 2003 Dec;17(12):2426-34
pubmed: 14523469
Nature. 2015 May 21;521(7552):357-61
pubmed: 25799995
Nat Commun. 2017 Oct 2;8(1):755
pubmed: 28970470
J Biol Chem. 1999 Nov 12;274(46):32662-6
pubmed: 10551821
Immunity. 2015 Feb 17;42(2):265-278
pubmed: 25680272
PLoS Comput Biol. 2015 Nov 25;11(11):e1004503
pubmed: 26606115
Blood. 2003 Jun 15;101(12):4944-51
pubmed: 12595313
J Immunol. 2006 Aug 1;177(3):1510-5
pubmed: 16849457
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
J Exp Med. 1997 Dec 1;186(11):1897-910
pubmed: 9382888
Blood. 2008 Feb 1;111(3):1497-503
pubmed: 18025150
Nature. 2005 Jun 2;435(7042):590-7
pubmed: 15931211
Nat Immunol. 2003 Jan;4(1):38-43
pubmed: 12436112
J Immunol. 1997 Feb 15;158(4):1650-9
pubmed: 9029101
Mol Cell Biol. 2005 Jun;25(12):4924-33
pubmed: 15923611
J Virol. 2000 Oct;74(19):9115-24
pubmed: 10982358
J Immunol. 1997 Jan 1;158(1):235-46
pubmed: 8977195
J Biol Chem. 1995 May 26;270(21):12659-64
pubmed: 7759516
Immunol Rev. 2000 Jun;175:158-74
pubmed: 10933601
Mod Pathol. 2006 Nov;19(11):1498-505
pubmed: 16980950
Cancer Cell. 2016 Jul 11;30(1):183
pubmed: 27479034
Nat Rev Cancer. 2018 Feb;18(2):103-116
pubmed: 29302068
Cancer Cell. 2015 Mar 9;27(3):409-25
pubmed: 25759025
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nat Rev Immunol. 2001 Oct;1(1):75-82
pubmed: 11905817
Cancer Cell. 2015 Jul 13;28(1):114-28
pubmed: 26073130
N Engl J Med. 2003 May 1;348(18):1764-75
pubmed: 12724482
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13266-71
pubmed: 16141323
Immunity. 1997 Apr;6(4):419-28
pubmed: 9133421
Immunity. 2000 Dec;13(6):817-27
pubmed: 11163197
EMBO J. 2012 Aug 1;31(15):3363-74
pubmed: 22728826
J Exp Med. 2005 Jun 6;201(11):1837-52
pubmed: 15939795
Haematologica. 2014 Jul;99(7):1138-48
pubmed: 24986876
Blood. 2007 Mar 1;109(5):2032-9
pubmed: 17038529
Nature. 1995 Nov 16;378(6554):303-6
pubmed: 7477353
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):726-34
pubmed: 16467082
Blood. 2002 Dec 15;100(13):4609-14
pubmed: 12393534
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2582-6
pubmed: 11226282
J Clin Invest. 1998 Oct 15;102(8):1515-25
pubmed: 9788964
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
Haematologica. 2003 Nov;88(11):1259-71
pubmed: 14607755
J Biol Chem. 2001 Jan 12;276(2):1474-8
pubmed: 11042164
Biochem Biophys Res Commun. 1994 Apr 15;200(1):28-34
pubmed: 7513161
J Clin Invest. 2005 Jun;115(6):1636-43
pubmed: 15902303
Nature. 1995 Nov 16;378(6554):298-302
pubmed: 7477352
J Biol Chem. 1996 Sep 13;271(37):22782-90
pubmed: 8798454
Blood. 2007 Jan 1;109(1):259-70
pubmed: 16985177