Mammalian Unc-51–like kinases 1 and 2 (ULK1 and ULK2) belong to the ULK/Atg1 family of serine/threonine kinases, which are conserved from yeast to mammals. Atg1 interacts with at least eight other proteins, some of which participate in autophagy (i.e., Atg17–Atg29–Atg31), and others exclusively participate in the Cvt pathway (i.e., Atg11–Atg20–Atg24 and Vac8). The activation of yeast Atg1 is linked to metabolic status via posttranslational modifications by energy sensors, including TORC1 and PKA. For example, phosphorylation of Atg13 by TORC1 reduces its binding affinity for Atg1 and Atg17, thereby limiting autophagy induction under nutrient-replete conditions. Mammalian ULK1 and ATG13 are phosphorylated by mTOR under normal growth conditions and are rapidly dephosphorylated in response to amino acid deprivation, thus activating ULK/ATG1 activity. Glucose and amino acid starvation also activate AMPK, leading to the phosphorylation of ULK1 and ULK2 at multiple sites within their unstructured serine–proline-rich domain. Thus, mTOR and AMPK cooperatively sense the metabolic cues and relay them to the ULK/ATG1 complex. ULK1 is also activated by the GSK3–TIP60-signaling axis upon growth factor deprivation. Alterations in ULK/Atg1 expression and autophagy-related functions have been implicated in the prognosis of some cancers.

References

1.Bo Wang,et al. Curr Opin Cell Biol. 2017 Apr; 45: 47–54.