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. 2022 Sep 7;14(18):4351. doi: 10.3390/cancers14184351

Figure 4.

Figure 4

Mechanisms for the constitutive activation of autophagy in PDAC cells. (A) Under nutrient-rich condition, the mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates microphthalmia (MiT)/transcription factor E (TFE), trapping these transcription factors in the cytosol. In PDAC cells, overexpression of IPO7 and IPO8 prevents mTORC1-mediated cytosolic retention of the MiT/TFE transcription factor [107]. (B) Under nutrient-rich condition, active mTORC1 phosphorylates ULK1 at S637, thus blocking ULK1-mediated autophagy initiation. In PDAC cells, the expression of Alpha4, a negative regulator of PP2A phosphatase activity, is downregulated. Thus, the PP2A-PRL64-β55α complex actively dephosphorylates S637 on ULK1, thereby counteracting mTORC1-mediated autophagy inhibition [114]. Note that both mechanisms allow PDAC cells to employ mTORC1-driven anabolic processes and autophagy-mediated nutrient recycling. Figure 4 is adapted from reference [41], the use of which is licensed under a Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/.