Kostenko O, Tsacoumangos A, Crooks D, Kil S J, Carlin C
The Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4970, USA.
Oncogene. 2006 Oct 26;25(50):6604-17. doi: 10.1038/sj.onc.1209675. Epub 2006 May 22.
Although combinatorial signaling through the ErbB network is implicated in certain types of human cancer, the specifics of how particular receptors contribute to the transformed phenotype are not well understood. The goal of this study was to identify epidermal growth factor (EGF) receptor-dependent cell signaling abnormalities specifically associated with mutations in a previously described 679-LL lysosomal sorting signal, which restrict ligand-dependent receptor downregulation by promoting recycling. Importantly, the 679-LL signal is not conserved in any of the other members of the ErbB receptor family suggesting its physiological function may be tightly regulated during EGF receptor-dependent signaling. Our data indicate that cells expressing receptors with an inactive 679-AA signal are rapidly transported to Rab4+ early endosomes after they are internalized in contrast to wild-type receptors that are localized to early endocytic antigen 1 (EEA1)+ early endosomes. Divergent trafficking in early endosomes is associated with prolonged activation of p44/42 mitogen-activated protein kinases (MAPK) but not Akt. Gab1 appears to be the critical signaling molecule facilitating prolonged MAPK signaling, and activated Gab1 is recruited to early endosomes in 679-AA receptor-expressing cells. Activated Gab1 is also recruited to early endosomes in breast cancer cells characterized by high levels of EGF receptor-ErbB2 heterodimers, suggesting 679-AA expressing cells recapitulate certain aspects of EGF receptor signaling and transformation by activated ErbB2. Phosphatidylinositol 3-kinase (PI3K)-dependent membrane translocation known to be important for maintaining Gab1 activity in other settings was dispensable. We conclude that 679-LL has dual functions in EGF receptor trafficking and threshold signaling through a subset of signaling molecules including p44/42 MAPK and Gab1.
尽管通过表皮生长因子受体（ErbB）网络的组合信号传导与某些类型的人类癌症有关，但特定受体如何促成转化表型的具体细节尚不清楚。本研究的目的是确定与先前描述的679-LL溶酶体分选信号中的突变特异性相关的表皮生长因子（EGF）受体依赖性细胞信号异常，该信号通过促进再循环来限制配体依赖性受体的下调。重要的是，679-LL信号在ErbB受体家族的任何其他成员中都不保守，这表明其生理功能可能在EGF受体依赖性信号传导过程中受到严格调控。我们的数据表明，与定位于早期内吞抗原1（EEA1）+早期内体的野生型受体相比，表达具有无活性679-AA信号的受体的细胞在被内化后迅速转运至Rab4+早期内体。早期内体中的不同运输与p44/42丝裂原活化蛋白激酶（MAPK）的延长激活有关，但与Akt无关。Gab1似乎是促进MAPK信号延长的关键信号分子，并且活化的Gab1被募集到表达679-AA受体的细胞的早期内体中。活化的Gab1也被募集到以高水平EGF受体-ErbB2异二聚体为特征的乳腺癌细胞的早期内体中，这表明表达679-AA的细胞概括了活化的ErbB2的EGF受体信号传导和转化的某些方面。已知对维持Gab1活性在其他情况下重要的磷脂酰肌醇3-激酶（PI3K）依赖性膜易位是不必要的。我们得出结论，679-LL在EGF受体运输和通过包括p44/42 MAPK和Gab1在内的一部分信号分子的阈值信号传导中具有双重功能。
