Serine 284 as a regulator of ERK2 dimerization and cellular localization
ABSTRACT: Signals conveyed through ERK1/2 Mitogen-Activated Protein Kinases are well-known to play a critical role in cancer initiation, progression, and therapy resistance. It has been demonstrated that the balance between ERK monomers and dimers and cytoplasmic and nuclear sub-signals are critical...
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| Formato: | tesis doctoral |
| Fecha de publicación: | 2020 |
| País: | España |
| Recursos: | Universidad de Cantabria (UC) |
| Repositorio: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.unican.es:10902/19195 |
| Acesso em linha: | http://hdl.handle.net/10902/19195 |
| Access Level: | acceso abierto |
| Palavra-chave: | Ser284 ERK dimerization Melanoma KSR1 IMP7 BRAF Vemurafenib Tumor progression Scaffold Cell signaling Dimerización de ERK Progresión tumoral Señalización celular |
| Resumo: | ABSTRACT: Signals conveyed through ERK1/2 Mitogen-Activated Protein Kinases are well-known to play a critical role in cancer initiation, progression, and therapy resistance. It has been demonstrated that the balance between ERK monomers and dimers and cytoplasmic and nuclear sub-signals are critical for the biological outcomes resulting from ERK activation subcellular distribution. Studying the efficacy of DEL22379, a new compound that blocks ERK dimerization, we made the startling observation that ERK dimerization was restricted to mammalians. A comparison of the ERK2 sequence through the evolutionary scale unveiled that Serine284 (H.sapiens) was conserved in those species in which ERK2 dimerized, being suggestive of playing some role in ERK2 dimerization. Indeed, we have shown that Ser284 is necessary but not sufficient for ERK2 dimerization. Moreover, Ser284 is a phosphorylatable residue of ERK2, being a cytoplasmic marker of active ERK2. This phosphorylation, mediated by MEK1 and AKT1, enhances ERK affinity for the scaffold KSR1 and reduces ERK2 interaction with nuclear shuttles like IMP7; being critical for the regulation of ERK2 subcellular distribution. In addition, the sensitivity to BRAF mutant melanoma cells to vemurafenib treatment correlates with higher levels of phospho-Ser284. Thus, p-Ser284 levels could be used as a predictive biomarker for the response to vemurafenib in BRAF positive melanoma patients. |
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