Unc-51 like autophagy activating kinase 1/2 (ULK1/2) (ULK1/2)

Unc-51 like autophagy activating kinase 1 and 2 (ULK1/2) are essential serine/threonine kinases that function as the primary initiators of the autophagy pathway in mammalian cells (UniProt O75385, Q8IYT8). They exist within a stable protein complex alongside ATG13, FIP200, and ATG101, acting as a critical node that integrates signals from the nutrient-sensing kinases mTORC1 and AMPK (PubMed: 21253019). Under conditions of nutrient abundance, mTORC1 phosphorylates and inhibits ULK1; however, during starvation or cellular stress, AMPK activates ULK1, which then phosphorylates the VPS34 complex to trigger autophagosome nucleation (PubMed: 21258367). In the context of disease, ULK1/2 are frequently exploited by cancer cells to survive metabolic stress and resist chemotherapy, making them attractive targets for inhibition in RAS-driven malignancies (PubMed: 34404836). Conversely, the activation of ULK1 is being investigated as a therapeutic strategy to clear protein aggregates in neurodegenerative diseases like Alzheimer's and Parkinson's (PubMed: 29233855). Small molecule inhibitors such as DCC-3116 are currently undergoing clinical evaluation to determine their efficacy in sensitizing tumors to MAPK pathway inhibitors (ClinicalTrials.gov: NCT04892501).

Other names

Unc-51 like autophagy activating kinase 1Unc-51 like autophagy activating kinase 2Autophagy-related protein 1 homologATG1ATG1AATG1BhATG1Unc51.1Unc51.2

Inhibition of ULK1/2 kinase activity to block the initiation of autophagy, thereby preventing cancer cell survival under metabolic stress; or activation of ULK1/2 to enhance the clearance of toxic protein aggregates in neurodegenerative conditions.