RESUMEN
Recently, the receptor for epidermal growth factor (EGF) was identified as a downstream element in different signaling pathways. This expanded its classical function as a receptor for EGF-like ligands to a role as mediator of diverse signaling systems and as a switch point of a cellular communication network. In addition, several downstream targets, (e.g. Smad proteins and STATs) into which signals from synergistic and antagonistic signaling pathways converge, were identified.
Asunto(s)
Factor de Crecimiento Epidérmico/fisiología , Receptores ErbB/fisiología , Transducción de Señal/fisiología , Animales , Apoptosis , Dimerización , Activación Enzimática , Receptores ErbB/química , Modelos Biológicos , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Fosfatasas/fisiologíaRESUMEN
The cross-talk between heterologous signalling systems of the cell represents a new dimension of complexity in the molecular communication network that governs a great variety of physiological processes. In pathophysiologically transformed cells, key elements of this network could offer unique opportunities for pharmacological intervention. In this article, the current state of knowledge regarding the role of epidermal growth factor (EGF) in such a network is described and the recent advances made in the elucidation of the mechanism underlying EGF receptor transactivation are discussed.
Asunto(s)
Receptores ErbB/metabolismo , Transducción de Señal/fisiología , Animales , Receptores ErbB/fisiología , Proteínas de Unión al GTP/fisiología , Humanos , Proteínas Tirosina Quinasas Receptoras/fisiologíaRESUMEN
In contrast to signal generation and transmission, the mechanisms and molecules that negatively regulate receptor tyrosine kinase (RTK) signaling are poorly understood. Here we characterize Mig-6 as a novel negative feedback regulator of the epidermal growth factor receptor (EGFR) and potential tumor suppressor. Mig-6 was identified in a yeast two-hybrid screen with the kinase active domain of the EGFR as bait. Upon EGF stimulation Mig-6 binds to the EGFR involving a highly acidic region between amino acids 985-995. This interaction is kinase activity-dependent, but independent of tyrosine 992. Mig-6 overexpression results in reduced activation of the mitogenactivated protein kinase ERK2 in response to EGF, but not FGF or PDGF, stimulation and in enhanced receptor internalization without affecting the rate of degradation. The induction of Mig-6 mRNA expression in response to EGF, but not FGF, indicates the existence of a negative regulatory feedback loop. Consistent with these findings, a possible role as tumor suppressor is indicated by Mig-6-mediated inhibition of EGFR overexpression-induced transformation of Rati cells.