Abstract
ARF role as tumor suppressor has been challenged in the last years by several findings of different groups ultimately showing that its functions can be strictly context dependent. We previously showed that ARF loss in HeLa cells induces spreading defects, evident as rounded morphology of depleted cells, accompanied by a decrease of phosphorylated Focal Adhesion Kinase (FAK) protein levels and anoikis. These data, together with previous finding that a PKC dependent signalling pathway can lead to ARF stabilization, led us to the hypothesis that ARF functions in cell proliferation might be regulated by phosphorylation. In line with this, we show here that upon spreading ARF is induced through PKC activation. A constitutive-phosphorylated ARF mutant on the conserved threonine 8 (T8D) is able to mediate both cell spreading and FAK activation. Finally, ARF-T8D expression confers growth advantage to cells thus leading to the intriguing hypothesis that ARF phosphorylation could be a mechanism through which pro-proliferative or anti proliferative signals could be transduced inside the cells in both physiological and pathological conditions.
Highlights
We previously demonstrated that ARF is regulated through the activation of PKC pathway in both cancer and transformed cell lines[15]
Mimicking the phosphorylation status of the protein is sufficient to drive its localization in the cytoplasm and to rescue spreading defect as well as Focal Adhesion Kinase (FAK) phosphorylation of ARF silencing in HeLa cells, resulting in an increased proliferative ability
To date the majority of studies on ARF has focused on its tumor suppressor roles, new evidences are paving the way to the hypothesis that ARF might promote survival
Summary
We previously demonstrated that ARF is regulated through the activation of PKC pathway in both cancer and transformed cell lines[15]. The T8D ARF mutant, that corresponds to the constitutive phosphorylation status of the protein, accumulates in the cytoplasm and is less efficient than the wt in halting cell proliferation These data led to the hypothesis that ARF function might be regulated by phosphorylation on this conserved residue. Mimicking the phosphorylation status of the protein is sufficient to drive its localization in the cytoplasm and to rescue spreading defect as well as FAK phosphorylation of ARF silencing in HeLa cells, resulting in an increased proliferative ability. Taken together these data indicate that PKC activation can prime ARF involvement in cell spreading leading to increased FAK activation and cell proliferation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
