THE ROLE OF KINASE-ACTIVITY AND THE KINASE INSERT REGION IN LIGAND-INDUCED INTERNALIZATION AND DEGRADATION OF THE C-FMS PROTEIN
THE ROLE OF KINASE-ACTIVITY AND THE KINASE INSERT REGION IN LIGAND-INDUCED INTERNALIZATION AND DEGRADATION OF THE C-FMS PROTEIN
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DOI：
10.1002/j.1460-2075.1991.tb08020.x
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发表时间：
1991-04-01
期刊：
影响因子：
11.4
通讯作者：
ROHRSCHNEIDER, L
中科院分区：
文献类型：
--
作者：
CARLBERG, K;TAPLEY, P;ROHRSCHNEIDER, L
通过追踪 M-CSF 结合后突变的 c-fms 分子的命运，分析了 c-fms 蛋白内吞和降解的分子步骤。缺乏酪氨酸激酶活性的突变 c-fms 蛋白在 M-CSF 结合后迅速内化，但不被降解。另一种缺乏大部分激酶插入区域的突变 c-fms 分子在 M-CSF 结合后同样被内化，并且也没有被降解。这表明内化信号与指导受体降解的信号是分开的。先前已表明，删除激酶插入结构域的 c-fms 突变体保留了酪氨酸激酶活性，但缺乏两个主要的自磷酸化位点。因此，降解步骤需要激酶活性和激酶插入区域，而内化步骤则独立于这些因素。接下来，对激酶插入区域内酪氨酸自磷酸化的主要位点进行突变，以确定 c-fms 激酶插入区域内的自磷酸化是否可能是触发内化受体降解的信号。这些突变受体在 M-CSF 的作用下仍会快速降解。因此，配体诱导的 c-fms 降解可能需要除 c-fms 受体本身之外的蛋白质的酪氨酸磷酸化，并且激酶插入区域可能是识别该底物所必需的。
Molecular steps in endocytosis and degradation of the c-fms protein were analyzed by following the fate of mutated c-fms molecules after M-CSF binding. A mutant c-fms protein lacking tyrosine kinase activity was rapidly internalized after M-CSF binding but not degraded. Another mutant c-fms molecule that lacked most of the kinase insert region was similarly internalized after M-CSF binding and also not degraded. This indicates that the signal for internalization is separate from that directing degradation of the receptor. It has been shown previously that a c-fms mutant in which the kinase insert domain is deleted retains tyrosine kinase activity but lacks two major sites of autophosphorylation. The degradation step therefore requires both kinase activity and the kinase insert region whereas the internalization step is independent of these factors. The major sites of tyrosine autophosphorylation within the kinase insert region were next mutated to determine whether autophosphorylation in the kinase insert region of c-fms might be the signal that triggers degradation of internalized receptors. These mutant receptors were still rapidly degraded in response to M-CSF. Therefore, ligand-induced degradation of c-fms may require tyrosine phosphorylation of a protein other than the c-fms receptor itself and the kinase insert region may be necessary for recognition of this substrate.