Regulation of the autophagy initiating kinase ULK1 by nutrients: roles of mTORC1 and AMPK.
TL;DR: This research presents a novel probabilistic approach to cell reprograming that allows for real-time, 3D image analysis of the response of the immune system to “foreign substance”.
Abstract: The serine/threonine kinase ULK1 is a mammalian homolog of AT G1, an upstream component of the core autophagy machinery. Studies in yeast AT G1 kinase complex demonstrate that the AT G1 kinase complex assembly is regulated by phosphorylaltion of AT G13 in a TORC1-dependent manner. However, the mammalian ULK1 complex appears to have different mechanisms of regulation because the mammalian ULK1-AT G13 association is not regulated by TORC1. Recently, we and Shaw’s group reported that AMPK phosphorylates ULK1 in response to cellular energy starvation to control ULK1 kinase function and autophagy induction. When nutrients are sufficient, mTORC1 phosphorylates ULK1, preventing its association and activation by AMPK. These studies have revealed a molecular mechanism of ULK1 regulation by nutrient signals via the coordinated actions of AMPK and mTORC1.
Citations
More filters
TL;DR: Recent literature is summarized and the potential of inflammation being the common causal mechanism to promote cancer promotion across cancer types is discussed.
246 citations
TL;DR: The functional significance of autophagy in cardiac ischemia reperfusion injury is reviewed and underlying signaling pathways are discussed to discuss underlying signalling pathways.
239 citations
Cites background from "Regulation of the autophagy initiat..."
...found that AMPK phosphorylation (Ser 317 and Ser 777) is required for ULK1 function in glucose starvation induced autophagy [16,17]....
[...]
TL;DR: It is suggested that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.
Abstract: Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mammalian target of rapamycin complex 1 (mTORC1) activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2(-/-) (tuberous sclerosis complex 2(-/-)) cells deprived of serum lipids exhibit a magnified unfolded protein response (UPR) but fail to appropriately expand their endoplasmic reticulum (ER), leading to inositol-requiring protein-1 (IRE1)-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly, we observed this phenotype in multiple human cancer cell lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.
167 citations
TL;DR: Mechanisms by which each mTOR complex might regulate cell survival in response to metabolic and other stresses are discussed.
Abstract: The mechanistic target of rapamycin (mTOR) kinase is a conserved regulator of cell growth, proliferation, and survival. In cells, mTOR is the catalytic subunit of two complexes called mTORC1 and mTORC2, which have distinct upstream regulatory signals and downstream substrates. mTORC1 directly senses cellular nutrient availability while indirectly sensing circulating nutrients through growth factor signaling pathways. Cellular stresses that restrict growth also impinge on mTORC1 activity. mTORC2 is less well understood and appears only to sense growth factors. As an integrator of diverse growth regulatory signals, mTOR evolved to be a central signaling hub for controlling cellular metabolism and energy homoeostasis, and defects in mTOR signaling are important in the pathologies of cancer, diabetes, and aging. Here we discuss mechanisms by which each mTOR complex might regulate cell survival in response to metabolic and other stresses.
160 citations
TL;DR: It is shown that AMP-activated protein kinase (AMPK) regulates autophagy by phosphorylating BECN1 at Thr388, uncovering a novel mechanism of Autophagy regulation.
Abstract: Macroautophagy/autophagy is a conserved catabolic process that recycles cytoplasmic material during low energy conditions. BECN1/Beclin1 (Beclin 1, autophagy related) is an essential protein for function of the class 3 phosphatidylinositol 3-kinase (PtdIns3K) complexes that play a key role in autophagy nucleation and elongation. Here, we show that AMP-activated protein kinase (AMPK) regulates autophagy by phosphorylating BECN1 at Thr388. Phosphorylation of BECN1 is required for autophagy upon glucose withdrawal. BECN1(T388A), a phosphorylation defective mutant, suppresses autophagy through decreasing the interaction between PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) and ATG14 (autophagy-related 14). The BECN1(T388A) mutant has a higher affinity for BCL2 than its wild-type counterpart; the mutant is more prone to dimer formation. Conversely, a BECN1 phosphorylation mimic mutant, T388D, has stronger binding to PIK3C3 and ATG14, and promotes higher autophagy activity than the wild-type control. These findings uncover a novel mechanism of autophagy regulation.
141 citations