EGFR下调
中文名称
通路描述
受体酪氨酸激酶（RTK）活性的调节涉及几乎所有细胞功能的控制。表皮生长因子受体（EGFR）是RTK中了解得最好的一个。生长因子可以与EGFR结合并激活它，启动细胞内的信号级联反应。EGFR也可招募到氯仿素包被的小窝中，这些小窝可内吞形成内吞囊泡。从那里，EGFR要么被回收回细胞膜，要么被导向溶酶体进行降解。这提供了一种机制，通过它EGFR信号被负向调节，并控制EGFR诱导信号的强度和持续时间。它还防止EGFR超激活，这在肿瘤发生中很常见。Cbl原癌基因可以负向调节EGFR信号。Cbl家族RING型泛素连接酶能够多泛素化EGFR，这是EGFR降解的关键步骤。所有Cbl蛋白都具有一个独特的结构域，可识别激活的EGFR上的磷酸化酪氨酸残基。它们还通过招募泛素连接酶来定向激活的EGFR的泛素化和降解。Cbl蛋白通过特异性靶向激活的EGFR并介导其下调，从而提供了一种通过负向调节信号过程的手段。Cbl还通过与其相互作用的上调蛋白CIN85（85kDa Cbl相互作用蛋白）促进受体内吞。CIN85通过其SH3结构域与Cbl结合，并被EGFR诱导的Cbl酪氨酸磷酸化增强。CIN85富含脯氨酸的区域与内吞蛋白相互作用，它们是氯仿素包被囊泡（CCVs）的调节成分。内吞蛋白与膜结合并诱导膜弯曲，与其他参与CCV形成的蛋白一起。CIN85快速招募内吞蛋白到激活的受体复合物是控制受体内吞的机制。
英文描述
EGFR downregulation Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis.
The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.
Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization.
The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.
Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization.
所含基因
30 个基因