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GSK-3 role in autophagy regulation has been studied in the past few years.Therefore, sequential phosphorylation of TSC2 by AMPK and GSK-3 occurs and these events may lead to mTOR pathway inhibition [67].Inoki and colleagues have also shown that GSK-3 inhibits mTOR pathway by phosphorylating the tumor suppressor TSC2 in an AMPK-priming phosphorylation-dependent manner.It has been clarified that GSK-3 regulates mTORC1 by phosphorylating the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Serine 859.GSK-3 inhibition reduces mTOR and raptor interaction leading to reduced phosphorylation of both p70S6K1 and ULK-1 and to increased autophagic flux [64].This occurs through GSK-3 dependent regulation of the transcription factor EB (TFEB), that is, a master regulator of autophagy and lysosomal biogenesis [65].or GSK-3?

GSK-3 role in autophagy regulation has been studied in the past few years. GSK-3 inhibits autophagy through the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). In fact, overexpression of either GSK-3α or GSK-3β activates mTORC1 and suppresses autophagy in MCF-7 breast cancer cells. Conversely, treating cells with GSK-3 inhibitors inhibits mTORC1 activity and increases autophagic flux [33]. It has been clarified that GSK-3 regulates mTORC1 by phosphorylating the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Serine 859. GSK-3 inhibition reduces mTOR and raptor interaction leading to reduced phosphorylation of both p70S6K1 and ULK-1 and to increased autophagic flux [64]. In human breast cancer cells, GSK-3 overexpression increases the autophagosome number by autophagic flux inhibition. This activity has been directly related to reduced lysosomal acidification triggered by GSK-3 [33]. Furthermore, GSK-3 inhibition induces prosurvival autophagy in human pancreatic cancer cells. This occurs through GSK-3 dependent regulation of the transcription factor EB (TFEB), that is, a master regulator of autophagy and lysosomal biogenesis [65]. In a prostate cancer cell model, inhibition of GSK-3β activity leads to a significant increase of AMP/ATP ratio, a strong trigger of AMPK activation, thus leading to autophagy induction [66]. Inoki and colleagues have also shown that GSK-3 inhibits mTOR pathway by phosphorylating the tumor suppressor TSC2 in an AMPK-priming phosphorylation-dependent manner. Therefore, sequential phosphorylation of TSC2 by AMPK and GSK-3 occurs and these events may lead to mTOR pathway inhibition [67]. GSK-3 commonly accepted involvement in autophagy regulation is schematically represented in