A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases

被引：222

作者：

Chen, Huaibin

Ma, Jinghong

Li, Wanqing

Eliseenkova, Anna V.

Xu, Chongfeng

Neubert, Thomas A.

Miller, W. Todd

Mohammadi, Moosa ^{[1
]}

机构：

[1] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA

[2] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA

[3] SUNY Stony Brook, Sch Med, Dept Physiol & Biophys, Stony Brook, NY 11794 USA

来源：

MOLECULAR CELL | 2007年 / 27卷 / 05期

关键词：

D O I：

10.1016/j.molcel.2007.06.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory "molecular brake" mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1 R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.

引用

页码：717 / 730

页数：14

共 51 条

[1] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[2] CHARACTERIZATION OF PP60(C-SRC) TYROSINE KINASE-ACTIVITIES USING A CONTINUOUS ASSAY - AUTOACTIVATION OF THE ENZYME IS AN INTERMOLECULAR AUTOPHOSPHORYLATION PROCESS [J].

BARKER, SC ;

KASSEL, DB ;

WEIGL, D ;

HUANG, XY ;

LUTHER, MA ;

KNIGHT, WB .

BIOCHEMISTRY, 1995, 34 (45) :14843-14851

[3] Distinct missense mutations of the FCFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype [J].

Bellus, GA ;

Spector, EB ;

Speiser, PW ;

Weaver, CA ;

Garber, AT ;

Bryke, CR ;

Israel, J ;

Rosengren, SS ;

Webster, MK ;

Donoghue, DJ ;

Francomano, CA .

AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (06) :1411-1421

[4] A RECURRENT MUTATION IN THE TYROSINE KINASE DOMAIN OF FIBROBLAST GROWTH-FACTOR RECEPTOR-3 CAUSES HYPOCHONDROPLASIA [J].

BELLUS, GA ;

MCINTOSH, I ;

SMITH, EA ;

AYLSWORTH, AS ;

KAITILA, I ;

HORTON, WA ;

GREENHAW, GA ;

HECHT, JT ;

FRANCOMANO, CA .

NATURE GENETICS, 1995, 10 (03) :357-359

[5] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[6] Allelic and locus heterogeneity in inherited venous malformations [J].

Calvert, JT ;

Riney, TJ ;

Kontos, CD ;

Cha, EH ;

Prieto, VG ;

Shea, CR ;

Berg, JN ;

Nevin, NC ;

Simpson, SA ;

Pasyk, KA ;

Speer, MC ;

Peters, KG ;

Marchuk, DA .

HUMAN MOLECULAR GENETICS, 1999, 8 (07) :1279-1289

[7] Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas [J].

Cappellen, D ;

De Oliveira, C ;

Ricol, D ;

de Medina, SGD ;

Bourdin, J ;

Sastre-Garau, X ;

Chopin, D ;

Thiery, JP ;

Radvanyi, F .

NATURE GENETICS, 1999, 23 (01) :18-20

[8]

CASNELLIE JE, 1991, METHOD ENZYMOL, V200, P115

[9]

CHESI M, 1997, NAT GENET, V3, P16

[10] PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib [J].

Corless, CL ;

Schroeder, A ;

Griffith, D ;

Town, A ;

McGreevey, L ;

Harrell, P ;

Shiraga, S ;

Bainbridge, T ;

Morich, J ;

Heinrich, MC .

JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (23) :5357-5364

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