RESUMO
Epidermal growth factor receptor (EGFR)-dependent signaling is involved in many physiological processes, and its deregulation leads to cellular dysfunctions and pathologies, of which cancer tops the list. Ubiquitin is the major determinant of EGFR fate all along the endocytic pathway, directly controlling EGFR signaling output. Indeed, the EGFR-ubiquitin network is often hijacked by cancer cells in order to have a proliferative advantage. In this chapter, we will review the different steps of EGFR activation and signal propagation, starting from the plasma membrane all the way down to the endosomal station, with a particular focus on the role of the ubiquitin system in controlling the balance between signal sustaining and downmodulation.
Assuntos
Endocitose , Receptores ErbB/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo , Animais , Receptores ErbB/química , Humanos , Neoplasias/metabolismo , UbiquitinaçãoRESUMO
Ubiquitination is a post-translational modification in which a small conserved peptide, ubiquitin, is appended to target proteins in the cell, through a series of complex enzymatic reactions. Recently, a particular form of ubiquitination, monoubiquitination, has emerged as a nonproteolytic reversible modification that controls protein function. In this review, we highlight recent findings on monoubiquitination as a signaling-induced modification, controlled, among others, by pathways originating from active receptor tyrosine kinases. Furthermore, we review the major cellular processes controlled by ubiquitin modification, including membrane trafficking, histone function, transcription regulation, DNA repair, and DNA replication.
Assuntos
Membrana Celular/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo , Animais , Reparo do DNA , Replicação do DNA , Endocitose , Anemia de Fanconi/metabolismo , Humanos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-cbl , Receptores Proteína Tirosina Quinases/metabolismo , Saccharomyces cerevisiae , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Lung cancer is the leading cause of cancer death worldwide. The epidermal growth factor receptor (EGFR) represents the main target for non-small cell lung cancer (NSCLC) therapy, as its overexpression or constitutive activation contributes to malignancy and correlates with poor prognosis. Our previous work demonstrated that in epithelial cells ß1 integrin is required for propagating EGFR signaling from the plasma membrane to the nucleus. In this study, we silenced ß1 integrin in human NSCLC A549 cells. The ß1 integrin-silenced cells show a defective activation of the EGFR signaling cascade, leading to decreased in vitro proliferation, enhanced sensitivity to cisplatin and Gefitinib, impaired migration and invasive behavior. Inhibitory effects on tumor growth and on the EGFR pathway were also observed in in vivo experiments. Moreover, ß1 integrin silencing increases the amount of EGFR on the cell surface, suggesting that ß1 integrin is required for efficient constitutive EGFR turnover at the cell membrane. Although the rate of EGF internalization and recycling is not affected in silenced cells, EGFR signaling is recovered only by expression of the Rab-coupling protein RCP, indicating that ß1 integrin sustains the endocytic machinery required for EGFR signaling. Overall, these results show that ß1 integrin is an essential regulator of EGFR signaling and tumorigenic properties of lung cancer cells, and that its silencing might represent an adjuvant approach to anti-EGFR therapy.