Deptor: not only a mTOR inhibitor

Abstract

Deptor is an important protein that belongs to the mTORC1 and mTORC2 complexes, able to interact with mTOR and to inhibit its kinase activity. As a natural mTOR inhibitor, Deptor is involved in several molecular pathways, such as cell growth, apoptosis, autophagy and ER stress response. For this reason, Deptor seems to play an important role in controlling cellular homeostasis. Despite several recent insights characterizing Deptor functions and regulation, its complete role within cells has not yet been completely clarified. Indeed, quite recently, Deptor has been associated with chromatin, and it has been demonstrated having a role in transcriptional regulation, controlling in such way endoplasmatic reticulum activity.From all these observations it is not surprising that Deptor can behave either as an oncogene or oncosuppressor, depending on the cell- or tissue-contexts. This review highlights recent progresses made in our understanding of the many activities of Deptor, describing its transcriptional and post-transcriptional regulation in different cancer cell types. Moreover, here we discuss the possibility of using compounds able to inhibit Deptor or to disrupt its interaction with mTOR as novel approaches for cancer therapy.

Keywords: Cancer; Cancer therapy; Deptor; ER homeostasis; mTOR.

Fig. 1

Structure of Deptor. Schematic illustrating Deptor structure: two DEP domains and a PDZ domain. Multiple phosphorylation sites are present between the C-terminal DEP domain and PDZ domain, where resides a consensus binding site, SSGYFS (Deptor degron)

Fig. 2

Structure homology of Deptor. Schematic representation of structural features of human Deptor and its orthologues

Fig. 3

Deptor is a natural mTOR inhibitor. Deptor interacts with and inhibits mTOR kinase activity, leading to the induction of autophagy process. At the same time, it also activates Akt pathway in order to promote cellular proliferation and survival

Fig. 4

Deptor depletion is associated with different pathway. The outcome of Deptor depletion depends on cellular context. In myocytes, loss of Deptor expression contributes to proliferation, whereas decreased levels of Deptor in other tissues mediate the apoptotic response by activating caspase 3 or enhancing ER stress