Fluctuations in AKT and PTEN Activity Are Linked by the E3 Ubiquitin Ligase cCBL

3-Poly-phosphoinositides (PIP<sub>3</sub>) regulate cell survival, division, and migration. Both PI3-kinase (phosphoinositide-3-kinase) and PTEN (phosphatase and tensin-homolog in chromosome 10) control PIP<sub>3</sub> levels, but the mechanisms connecting PI3-kinase and PTEN...

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Autores principales: Manuel Olazábal-Morán, Miriam Sánchez-Ortega, Laura Martínez-Muñoz, Carmen Hernández, Manuel S. Rodríguez, Mario Mellado, Ana C. Carrera
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
CBL
AKT
Acceso en línea:https://doaj.org/article/ffa2fdd3b6c6481f85c696403eaaae8b
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Sumario:3-Poly-phosphoinositides (PIP<sub>3</sub>) regulate cell survival, division, and migration. Both PI3-kinase (phosphoinositide-3-kinase) and PTEN (phosphatase and tensin-homolog in chromosome 10) control PIP<sub>3</sub> levels, but the mechanisms connecting PI3-kinase and PTEN are unknown. Using non-transformed cells, the activation kinetics of PTEN and of the PIP<sub>3</sub>-effector AKT were examined after the addition of growth factors. Both epidermal growth factor and serum induced the early activation of AKT and the simultaneous inactivation of PTEN (at ~5 min). This PIP<sub>3</sub>/AKT peak was followed by a general reduction in AKT activity coincident with the recovery of PTEN phosphatase activity (at ~10–15 min). Subsequent AKT peaks and troughs followed. The fluctuation in AKT activity was linked to that of PTEN; PTEN reconstitution in PTEN-null cells restored AKT fluctuations, while PTEN depletion in control cells abrogated them. The analysis of PTEN activity fluctuations after the addition of growth factors showed its inactivation at ~5 min to be simultaneous with its transient ubiquitination, which was regulated by the ubiquitin E3 ligase cCBL (casitas B-lineage lymphoma proto-oncogene). Protein-protein interaction analysis revealed cCBL to be brought into the proximity of PTEN in a PI3-kinase-dependent manner. These results reveal a mechanism for PI3-kinase/PTEN crosstalk and suggest that cCBL could be new target in strategies designed to modulate PTEN activity in cancer.