Referencia

Lafarga et al (2011) EmboJournal 31(4):856-859

Autores

Vanesa Lafarga, Ivette Aymerich, Olga Tapia, Federico Mayor Jr, Petronila Penela

Resumen

Cell motility and adhesion involves dynamic microtubule (MT) acetylation/deacetylation, a process regulated by enzymes as HDAC6, a major cytoplasmic α-tubulin deacetylase. We identify G protein-coupled receptor kinase 2 (GRK2) as a key novel stimulator of HDAC6. GRK2, which levels inversely correlate with the extent of α-tubulin acetylation in epithelial cells and fibroblasts, directly associates with and phosphorylates HDAC6 to stimulate α-tubulin deacetylase activity. Remarkably, phosphorylation of GRK2 itself at S670 specifically potentiates its ability to regulate HDAC6. GRK2 and HDAC6 colocalize in the lamellipodia of migrating cells, leading to local tubulin deacetylation and enhanced motility. Consistently, cells expressing GRK2-K220R or GRK2-S670A mutants, unable to phosphorylate HDAC6, exhibit highly acetylated cortical MTs and display impaired migration and protrusive activity. Finally, we find that a balanced, GRK2/HDAC6-mediated regulation of tubulin acetylation differentially modulates the early and late stages of cellular spreading. This novel GRK2/HDAC6 functional interaction may have important implications in pathological contexts.

Descripción

La migración y adhesión celular dependen de la dinámica de acetilación/deacetilacion de los microtubulos, proceso regulado por la deacetilasa HDAC6. En este trabajo se demuestra que en respuesta a diferentes estímulos quiomiotácticos la quinasa GRK2 estimula la actividad tubulina-deacetilasa de HDAC6 favoreciendo así la migración de células epiteliales y fibroblastos y modulando la cinética de “spreading”. Este nuevo mecanismo de regulación de HDAC6 por GRK2 puede ser también fundamental para otros procesos que contribuyan a la malignidad celular, tales como la resistencia a estrés celular y citotoxicidad, señalando a GRK2 como una potencial diana terapeútica.

Foto grupo marzo

REFERENCIA DEL GRUPO INVESTIGADOR
El grupo de señalización celular liderado por Federico Mayor Menéndez y Petronila Penela se encuentra en el Centro de Biología Molecular “Severo Ochoa” (CSIC-Universidad Autónoma de Madrid) y también forma parte del Instituto de Investigación Sanitaria La Princesa. Vanesa Lafarga es contratada del Programa JAE-Doc del CSIC. El grupo se centra en el estudio de la familia de quinasas GRKs (G protein-coupled receptor kinases), que constituyen importantes nodos en las redes de transducción de señales, con el objetivo de identificar el interactoma de GRKs relevante en distintos tipos celulares y/o contextos fisio-patológicos y de evaluar el impacto funcional de cambios en los niveles de GRKs en patologías cardiovasculares, inflamatorias, diabetes/obesidad o progresión tumoral.

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