Identification of a functional interaction between the transmembrane protein smoothened and the Kinesin-related protein Costal2
Identification of a functional interaction between the transmembrane protein smoothened and the Kinesin-related protein Costal2
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DOI：
10.1016/j.cub.2003.10.004
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发表时间：
2003-11-11
期刊：
影响因子：
9.2
通讯作者：
Robbins, DJ
中科院分区：
文献类型：
--
作者：
Ogden, SK;Ascano, M;Robbins, DJ
Hhedgehog(HH)家族在许多后生动物结构的发展中起着重要的指导作用[1]。与HH同系物在决定细胞命运中所扮演的角色一致，异常的HH信号导致了许多人类的病理。当HH与其受体补丁(PTC)[2，3]结合，激活跨膜蛋白Smoothned(Smo)[4，5]时，HH信号转导开始。SMO将激活信号传递给微管相关的Hedgehog信号复合体(HSC)。至少，HSC由激动素相关蛋白Costa2(Cos2)、蛋白激酶融合蛋白(FU)和转录因子Cubitus interruptus(Ci)组成[6-11]。作为对HSC激活的响应，Ci的抑制物和激活物形式之间的比率被改变，从而决定了各种HH靶基因的表达水平[11-13]。Smo激活和向HSC发送信号之间的步骤尚未描述。在这里，我们描述了Smo和Cos2之间的功能相互作用，这是HH信号转导所必需的。我们认为这种相互作用是直接的，并允许激活CI以响应HH。这项工作填补了我们对HH信号转导途径理解的最后一个主要空白，它表明连接Smo和HSC不需要中间信号。
The hedgehog (Hh) family of morphogens plays important instructional roles in the development of numerous metazoan structures [1]. Consistent with the role Hh homologs play in cell fate determination, aberrant Hh signaling results in numerous human pathologies. Hh signal transduction is initiated when Hh binds to its receptor Patched (Ptc) [2, 3], activating the transmembrane protein Smoothened (Smo)[4, 5]. Smo transmits its activation signal to a microtubule-associated Hedgehog signaling complex (HSC). At a minimum, the HSC consists of the Kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the transcription factor Cubitus interruptus (Ci) [6-11]. In response to HSC activation, the ratio between repressor and activator forms of Ci is altered, determining the expression levels of various Hh target genes [11-13]. The steps between Smo activation and signaling to the HSC have not been described. Here, we describe a functional interaction between Smo and Cos2, which is necessary for Hh signaling. We propose that this interaction is direct and allows for activation of Ci in response to Hh. This work fills in the last major gap in our understanding of the Hh signal transduction pathway by suggesting that no intermediate signal is required to connect Smo to the HSC.