Abstract
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.
Highlights
PIP3, the product of PI3-kinase and its effector AKT, are essential mediators of cell survival [1,2,3,4]
Endo-phosphatase and tensin-homolog in chromosome 10’ (PTEN) activity was tested in parallel and a similar fluctuation seen, with a reduction at ~5 min and a second at ~30–60 min following the addition of FCS (Figure 1b)
The present results reveal a mechanism for the control of endogenous PTEN activity upon the addition of growth factor (GF)
Summary
PIP3 (phosphoinositide 3,4,5P3), the product of PI3-kinase and its effector AKT, are essential mediators of cell survival [1,2,3,4]. Somatic mutations in PTEN are frequent in cancer, as is the loss of function of one PTEN allele. The latter is seen in patients with hereditary PHTS syndrome (PTEN hamartoma tumor syndrome) who are more susceptible to the appearance of tumors [5,6,7]. Post-translational modifications are effective in inducing rapid and transient alterations in the architecture, localization, and activity of PTEN. These include C-terminal PTEN phosphorylation, which triggers an enzyme inactive conformation; PTEN sumoylation, which increases its localization to the plasma membrane (PM); and PTEN ubiquitination, which can influence PTEN stability, activity, and localization [10,11,12]
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