The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations.
The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations.
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DOI：
10.1126/scisignal.2000021
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发表时间：
2009-02-17
影响因子：
7.3
通讯作者：
Schlessinger J
中科院分区：
文献类型：
--
作者：
Lew ED;Furdui CM;Anderson KS;Schlessinger J
成纤维细胞生长因子受体1（FGFR1）酪氨酸激酶结构域的自磷酸化是由一个顺序和精确有序的三阶段自磷酸化反应介导的。激活环酪氨酸的第一阶段自磷酸化导致激酶活性的50至100倍刺激，然后是三个额外的酪氨酸残基的第二阶段磷酸化，这些残基是信号分子的结合位点。最后，第二活化环酪氨酸的第三阶段磷酸化导致FGFR 1催化活性的额外10倍刺激。在这份报告中，我们表明，连续的自磷酸化的FGFR1激酶结构域中的5个酪氨酸是动力学控制下，介导的氨基酸序列周围的酪氨酸和它们的位置内的激酶结构，而且，磷酰基转移是限速步骤。此外，自磷酸化的严格顺序被激酶结构域中的胶质母细胞瘤来源的致癌FGFR1点突变破坏。我们提出，致癌和其他激活FGFR突变引起的酪氨酸自磷酸化的破坏性逐步激活可能导致激活受体的信号分子的异常激活和组装。
Autophosphorylation of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1) is mediated by a sequential and precisely ordered three-stage autophosphorylation reaction. First-stage autophosphorylation of an activation loop tyrosine leads to 50- to 100-fold stimulation of kinase activity and is followed by second-stage phosphorylation of three additional tyrosine residues, which are binding sites for signaling molecules. Finally, third-stage phosphorylation of a second activation loop tyrosine leads to an additional 10-fold stimulation of FGFR1 catalytic activity. In this report, we show that sequential autophosphorylation of five tyrosines in the FGFR1 kinase domain is under kinetic control, mediated by both the amino acid sequence surrounding the tyrosines and their locations within the kinase structure and, moreover, that phosphoryl transfer is the rate-limiting step. Furthermore, the strict order of autophosphorylation is disrupted by a glioblastoma-derived, oncogenic FGFR1 point mutation in the kinase domain. We propose that disrupted stepwise activation of tyrosine autophosphorylation caused by oncogenic and other activating FGFR mutations may lead to aberrant activation of and assembly of signaling molecules by the activated receptor.
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ABL酪氨酸激酶结构域中的SRC样不活跃构象。
影响因子：
9.8
作者：
Levinson NM;Kuchment O;Shen K;Young MA;Koldobskiy M;Karplus M;Cole PA;Kuriyan J
通讯作者：
Kuriyan J
影响因子：
11.4
作者：
Hubbard, SR
通讯作者：
Hubbard, SR
影响因子：
2.9
作者：
Ablooglu, AJ;Kohanski, RA
通讯作者：
Kohanski, RA
影响因子：
5.7
作者：
Till, JH;Becerra, M;Hubbard, SR
通讯作者：
Hubbard, SR
影响因子：
15
作者：
Valiev, M;Kawai, R;Weare, JH
通讯作者：
Weare, JH