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

Manuel Olazábal-Morán (1) , Miriam Sánchez-Ortega (1) , Laura Martínez-Muñoz (1) , Carmen Hernández (1) , Manuel S Rodríguez (2, 3) , Mario Mellado (1) , Ana C Carrera (1)

1 CNB-CSIC - Centro Nacional de Biotecnología [Madrid]
2 ITAV - Institut des Technologies Avancées en sciences du Vivant
3 LCC - Laboratoire de chimie de coordination

3-Poly-phosphoinositides (PIP3) regulate cell survival, division, and migration. Both PI3-kinase (phosphoinositide-3-kinase) and PTEN (phosphatase and tensin-homolog in chromosome 10) control PIP3 levels, but the mechanisms connecting PI3-kinase and PTEN are unknown. Using non-transformed cells, the activation kinetics of PTEN and of the PIP3-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 PIP3/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.

Mots clés: PTEN; CBL; E3 ubiquitin ligase; Phosphatidylinositide 3-kinase; AKT

Domaines: Biochimie, Biologie Moléculaire

Manuel Olazábal-Morán, Miriam Sánchez-Ortega, Laura Martínez-Muñoz, Carmen Hernández, Manuel S Rodríguez, et al.. Fluctuations in AKT and PTEN Activity Are Linked by the E3 Ubiquitin Ligase cCBL. Cells, 2021, 10 (11), pp.2803. ⟨10.3390/cells10112803⟩. ⟨hal-03728095⟩