AMBRA1: When autophagy meets cell proliferation

Abstract

A growing amount of evidence reported in the literature in recent years strongly supports the relevance of the interplay between autophagy and other pathways. In this context, the study of the link between autophagy and cell proliferation regulation has been among the most challenging. In our recent publications, we finely characterize a role for the pro-autophagic protein AMBRA1 in the regulation of cell proliferation. AMBRA1 modulates autophagy and interacts with PPP2/PP2A (protein phosphatase 2), thus also modulating MYC protein levels and the cell proliferation rate. Interestingly, this pathway of regulation is controlled by the master regulator of autophagy and cell growth, MTORC1. Notably, in our study we demonstrate the relevance of the AMBRA1-mediated regulation of MYC in tumorigenesis, also identifying AMBRA1 as a tumor suppressor gene.

Keywords: MTORC1; MYC; PPP2/PP2A; cancer.

Figure 1.

AMBRA1-mediated regulation of MYC and its interplay with the autophagy pathway. We recently demonstrated that AMBRA1 enhances PPP2/PP2A phosphatase activity on phospho-Ser62 of MYC, resulting in the proteasomal degradation of the transcription factor and in preventing hyperproliferation and tumorigenesis. By contrast, the oncogene KIAA1524/CIP2A inhibits the activity of PPP2 in the same pathway. We also found that the AMBRA1-PPP2 role in MYC dephosphorylation is under MTORC1 control. Intriguingly, numerous crosstalk and feedback mechanisms between complexes regulating this pathway (MTORC1, AMBRA1-PPP2, KIAA1524/CIP2A-PPP2) and autophagy have been reported (see the figure for more details), supporting the evidence that autophagy and cell proliferation regulation are tightly coordinated.