STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family
STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family
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DOI：
10.1002/j.1460-2075.1996.tb00973.x
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发表时间：
1996-11-01
期刊：
影响因子：
11.4
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Iwama, A;Yamaguchi, N;Suda, T
STK/RON酪氨酸激酶是肝细胞生长因子（HGF）受体家族的一员，是巨噬细胞刺激蛋白（MSP）的受体。为了研究STK/RON信号通路，我们制备了STK/RON转染物，在生长方面表现出相反的特征，表达STK/RON的Ba/F3 pro-B细胞（BaF/STK）表现出MSP依赖性生长，而表达STK/RON的小鼠红白血病细胞（MEL/STK）表现出MSP诱导的凋亡。这种细胞凋亡伴随着c-Jun n -末端激酶（JNK）的延长激活，该激酶最近被认为与细胞凋亡的启动有关。共免疫沉淀分析显示，在两种转基因中，自磷酸化的STK/RON与plc - γ、pi3 -激酶、Shc和Grb2相关。然而，在MEL/STK细胞中，主要的酪氨酸磷酸化蛋白p61和p65与STK/RON特异性相关，两个c-末端酪氨酸残基Y1330和Y1337发生突变。在HGF受体多功能对接位点的对偶体中，抑制msp诱导的生长和凋亡，对这些突变体和体外关联的分析表明，包括p61和p65在内的信号蛋白直接结合在多功能对接位点的磷酸酪氨酸上。这些结果表明，细胞生长的正或负信号是通过多功能对接位点产生的，并表明p61和p65以及JNK参与细胞凋亡。我们的发现首次证明了细胞凋亡是通过受体酪氨酸激酶产生的。
STK/RON tyrosine kinase, a member of the hepatocyte growth factor (HGF) receptor family, is a receptor for macrophage-stimulating protein (MSP), To examine the STK/RON signalling pathway, we generated STK/RON transfectants showing opposite features in growth, STK/RON-expressing Ba/F3 pro-B cells (BaF/STK) exhibited MSP-dependent growth, whereas STK/RON-expressing mouse erythroleukaemia cells (MEL/STK) displayed MSP-induced apoptosis, This apoptosis was accompanied by the prolonged activation of c-Jun N-terminal kinase (JNK), which has recently been implicated in the initiation of apoptosis, Co-immunoprecipitation analyses showed that autophosphorylated STK/RON associated with PLC-gamma, PI3-kinase, Shc and Grb2 in both transfectants, However, major tyrosine-phosphorylated proteins, p61 and p65, specifically associated with STK/RON in MEL/STK cells, Mutations at two C-terminal tyrosine residues, Y1330 and Y1337, in the counterpart of the multifunctional docking site of the HGF receptor abolished both MSP-induced growth and apoptosis, Analyses of these mutants and in vitro association revealed that signalling proteins including p61 and p65 directly bound to the phosphotyrosines in the multifunctional docking site. These results demonstrate that positive or negative signals toward cell growth are generated through the multifunctional docking site and suggest the involvement of p61 and p65 as well as JNK in apoptosis, Our findings provide the first evidence for apoptosis via a receptor tyrosine kinase.