RESUMEN
Epidermal growth factor (EGF) activates the EGF receptor (EGFR) and stimulates its internalization and trafficking to lysosomes for degradation. However, a percentage of EGFR undergoes ligand-independent endocytosis and is rapidly recycled back to the plasma membrane. Importantly, alterations in EGFR recycling are a common hallmark of cancer, and yet, our understanding of the machineries controlling the fate of endocytosed EGFR is incomplete. Intersectin-s is a multi-domain adaptor protein that is required for internalization of EGFR Here, we discover that intersectin-s binds DENND2B, a guanine nucleotide exchange factor for the exocytic GTPase Rab13, and this interaction promotes recycling of ligand-free EGFR to the cell surface. Intriguingly, upon EGF treatment, DENND2B is phosphorylated by protein kinase D and dissociates from intersectin-s, allowing for receptor targeting to degradation. Our study thus reveals a novel mechanism controlling the fate of internalized EGFR with important implications for cancer.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Membrana Celular/metabolismo , Endocitosis , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/efectos de los fármacos , Receptores ErbB/genética , Factores de Intercambio de Guanina Nucleótido/genética , Células HEK293 , Humanos , Neoplasias/fisiopatología , Fosforilación , Unión Proteica , Proteína Quinasa C/metabolismo , Transporte de Proteínas , Proteínas Supresoras de Tumor/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
BACKGROUND: Hematologic markers, such as the neutrophil-to-lymphocyte ratio (NLR), characterize the inflammatory response to cancer and are associated with poorer survival in various malignancies. We evaluate the effect of pretreatment NLR on overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Using multiple databases, a systematic search for articles evaluating the effect of NLR on OS in patients with HNSCC was performed. An inverse variation, random-effects model was used to analyze the data. RESULTS: A total of 24 of 241 articles, including 6479 patients, were analyzed. The combined hazard ratio for OS in patients with an elevated NLR (range 2.04-5) was 1.78 (confidence interval [CI] 1.53-2.07; P < .0001). The hazard ratios for site-specific cancer: oral cavity 1.56 CI 1.23-1.98 (P < .001), nasopharynx 1.66 CI 1.35-2.04 (P < .001), larynx 1.55 CI 1.26-1.92 (P < .001), and hypopharynx 2.36 CI 1.54-3.61 (P < .001). CONCLUSION: An elevated NLR is predictive of poorer OS in patients with HNSCC.