Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation
Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation
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DOI：
10.1128/mcb.20.5.1537-1545.2000
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发表时间：
2000-03-01
影响因子：
5.3
通讯作者：
Skolnik, EY
中科院分区：
文献类型：
--
作者：
Becker, E;Huynh-Do, U;Skolnik, EY
哺乳动物Ste 20激酶Nck相互作用激酶（NIK）特异性激活c-Jun氨基末端激酶（JNK）促分裂原活化蛋白激酶模块。NIK还结合SH 2/SH 3衔接蛋白Nck的SH 3结构域。为了确定Nck是否作为接头将NIK偶联到受体酪氨酸激酶信号通路，我们确定NIK是否被Eph受体（EphR）激活，EphR构成受体酪氨酸激酶（RTK）的最大家族，并且该家族的成员在神经和血管系统的模式化中起重要作用。我们表明，在由两种EphR EphB 1和EphB 2刺激的细胞中，NIK激酶活性特异性地增加。EphB 1激酶活性和在所有Eph受体中保守的质膜酪氨酸（Y 594）的磷酸化对于EphB 1激活NIK都是关键的，尽管EphB 1 R中的pY 594先前已显示结合Nck的SH 2结构域，但我们发现EphB 1和EphB 2的刺激主要导致NIK/Nck、p62（dok）、RasGAP和未鉴定的145-kDa酪氨酸磷酸化蛋白之间的复合物，酪氨酸磷酸化的p62（dok）最有可能直接结合Nck和RasGAP的SH 2结构域，并间接结合Nck SH 3结构域的NIK。我们发现NIK活化对于将EphB 1 R偶联至生物反应也是关键的，所述生物反应包括通过EphB 1活化整联蛋白和JNK。总之，这些发现支持了这样的模型，其中通过Nck将Ste 20激酶NIK募集至含磷酸酪氨酸的蛋白质是EphR下游信号级联中的重要近端步骤。
The mammalian Ste20 kinase Nck-interacting kinase (NIK) specifically activates the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase module. NIK also binds the SH3 domains of the SH2/SH3 adapter protein Nck. To determine whether Nck functions as an adapter to couple NIK to a receptor tyrosine kinase signaling pathway, we determined whether NIK is activated by Eph receptors (EphR), EphRs constitute the largest family of receptor tyrosine kinases (RTK), and members of this family play important roles in patterning of the nervous and vascular systems, In this report, we show that NIK kinase activity is specifically increased in cells stimulated by two EphRs, EphB1 and EphB2, EphB1 kinase activity and phosphorylation of a juxtamembrane tyrosine (Y594), conserved in all Eph receptors, are both critical for NIK activation by EphB1, Although pY594 in the EphB1R has previously been shown to bind the SH2 domain of Nck, we found that stimulation of EphB1 and EphB2 led predominantly to a complex between NIK/Nck, p62(dok), RasGAP, and an unidentified 145-kDa tyrosine-phosphorylated protein, Tyrosine-phosphorylated p62(dok) most probably binds directly to the SH2 domain of Nck and RasGAP and indirectly to NIK bound to the SH3 domain of Nck. We found that NIK activation is also critical for coupling EphB1R to biological responses that include the activation of integrins and JNK by EphB1, Taken together, these findings support a model in which the recruitment of the Ste20 kinase NIK to phosphotyrosine-containing proteins by Nck is an important proximal step in the signaling cascade downstream of EphRs.