The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site.
The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site.
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DOI：
10.1016/j.cell.2009.05.028
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发表时间：
2009-08-07
期刊：
影响因子：
64.5
通讯作者：
Schlessinger J
中科院分区：
文献类型：
--
作者：
Bae JH;Lew ED;Yuzawa S;Tomé F;Lax I;Schlessinger J
SH2结构域介导的相互作用代表了受体酪氨酸激酶的跨膜信号传导的关键步骤。不考虑并可能代表过度简化的机制，用于调节活细胞中信号通路的选择性。磷脂酶Cγ片段中FGFR1活化酪氨酸激酶结构域的晶体结构在SH2域和FGFR1激酶域中的区域上以磷酸化的方式揭示了一种机制。 SH2结构域的选择性在体内受到调节，以介导特定的细胞过程。
SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY containing peptides may not account for and likely represents an oversimplified mechanism for regulation of selectivity of signaling pathways in living cells. Here we describe the crystal structure of the activated tyrosine kinase domain of FGFR1 in complex with a phospholipase Cγ fragment. The structural and biochemical data and experiments with cultured cells show that the selectivity of phospholipase Cγ binding and signaling via activated FGFR1 are determined by interactions between a secondary binding site on an SH2 domain and a region in FGFR1 kinase domain in a phosphorylation independent manner. These experiments reveal a mechanism for how SH2 domain selectivity is regulated in vivo to mediate a specific cellular process.