ULK1

Last updated
ULK1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ULK1 , ATG1, ATG1A, UNC51, Unc51.1, hATG1, unc-51 like autophagy activating kinase 1
External IDs OMIM: 603168; MGI: 1270126; HomoloGene: 2640; GeneCards: ULK1; OMA:ULK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8408

22241

Ensembl

ENSG00000177169

ENSMUSG00000029512

UniProt

O75385

O70405

RefSeq (mRNA)

NM_003565

NM_009469
NM_001347394

RefSeq (protein)

NP_003556

NP_001334323
NP_033495

Location (UCSC) Chr 12: 131.89 – 131.92 Mb Chr 5: 110.93 – 110.96 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Serine/threonine-protein kinase ULK1 is an enzyme that in humans is encoded by the ULK1 gene. [5] [6]

Contents

Unc-51-like autophagy-activating kinases 1 and 2 (ULK1/2) are two similar isoforms of an enzyme that in humans is encoded by the ULK1/2 genes. [7] [8] The enzyme is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded. [9]

Function

Ulk1/2 is an important protein in autophagy for mammalian cells, and is homologous to ATG1 in yeast. It is part of the ULK1-complex, which is needed in early steps of autophagosome biogenesis. The ULK1 complex also consists of the FAK family kinase interacting protein of 200 kDa (FIP200 or RB1CC1) and the HORMA (Hop/Rev7/Mad2) domain-containing proteins ATG13 and ATG101. [10] ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy. [11] However, ULK1 and ULK2 show high functional redundancy; studies have shown that ULK2 can compensate for the loss of ULK1. Nutrient dependent autophagy is only fully inhibited if both ULK1 and ULK2 are knocked out.

ULK1 has many downstream phosphorylation targets to aid in this induction of the isolation membrane/ autophagosome. Recently, a mechanism for autophagy has been elucidated. Models have proposed that the active ULK1 directly phosphorylates Beclin-1 at Ser 14 and activates the pro-autophagy class III phosphoinositide 3-kinase (PI(3)K), VPS34 complex, to promote autophagy induction and maturation. [12]

Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals. [13]

Ulk1/2 may have critical roles beyond what ATG1 performs in yeast, including neural growth and development.

Interactions

When active, mTORC1 inhibits autophagy by phosphorylating both ULK1 and ATG13, which reduces the kinase activity of ULK1. Under starvation conditions, mTORC1 is inhibited and dissociates from ULK1 allowing it to become active. AMPK is activated when intracellular AMP increases under starvation conditions, which inactivate mTORC1, and thus indirectly activate ULK1. AMPK also directly phosphorylates ULK1 at multiple sites in the linker region between the kinase and C-terminal domains. [10]

ULK1 can phosphorylate itself as well as ATG13 and RB1CC1, which are regulatory proteins; however, the direct substrate of ULK1 has not been identified although recent studies suggest it phosphorylates Beclin-1.[ citation needed ]

Upon proteotoxic stresses, ULK1 has been found to phosphorylate the adaptor protein p62/SQSTM1, which increases the binding affinity of p62/SQSTM1 for ubiquitin. [10] [14]

ULK1 has been shown to interact with Raptor, Beclin1, Class-III-PI3K, GABARAPL2, [15] GABARAP, [15] [16] SYNGAP1 [17] and SDCBP. [17]

Structure

ULK1 is a 112-kDa protein. It contains a N-terminal kinase domain, a serine-proline rich region, and a C-terminal interacting domain. The serine-proline rich region has been shown experimentally to be the site of phosphorylation by mTORC1 and AMPK—a negative and positive regulator of ULK1 activity, respectively. The C-terminal domain contains two microtubule-interacting and transport (MIT) domains and acts as a scaffold which links ULK1, ATG13, and FIFP200 together to form a complex that is essential to initiate autophagy. Early autophagy targeting/tethering (EAT) domains in the C-terminus are arranged as MIT domains consisting of two three-helix bundles. MIT domains also mediate interactions with membranes. The N-terminus contains a serine-threonine kinase domain. ULK1 also contains a large activation loop between the N and C terminus that is positively charged. This region may regulate kinase activity and play a role in recognizing different substrates. ULK1 and ULK2 share significant homology in both the C-terminal and N-terminal domains. [11]

Post-translational modifications

ULK1 is phosphorylated by AMPK on Ser317 and Ser777 to activate autophagy; mTOR participates in inhibitory phosphorylation of ULK1 on Ser757. [18] Additionally, ULK1 can auto-phosphorylate itself at Thr180 to facilitate self activation. [19]

Viral targeting of ULK1 appears to disrupt host autophagy. Coxsackievirus B3 viral proteinase 3C can proteolytically process ULK1 by cleaving after glutamine (Q) residue 524, separating the N-terminal kinase domain from C-terminal early autophagy targeting/tethering (EAT) domain. [20]

Given ULK1's role in autophagy, many diseases such as cancer, [21] neurodegenerative disorders, neurodevelopment disorders, [22] and Crohn's disease [23] could be attributed to any impairments in autophagy regulation.

In cancer specifically, ULK1 has become an attractive therapeutic target.[ citation needed ] Since autophagy acts as a cell survival trait for cells, it enables tumors (once they are already formed) to survive energy deprivation and other stresses such as chemotherapeutics. For that reason, inhibiting autophagy may prove to be beneficial. Thus, inhibitors have been targeted towards ULK1. [24]

Related Research Articles

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

<span class="mw-page-title-main">ATM serine/threonine kinase</span> Mammalian protein found in Homo sapiens

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">CHEK2</span> Protein-coding gene in humans

CHEK2 is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.

<span class="mw-page-title-main">Folliculin</span> Protein-coding gene

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

<span class="mw-page-title-main">STK11</span> Protein-coding gene in the species Homo sapiens

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.

<span class="mw-page-title-main">P70-S6 Kinase 1</span> Protein-coding gene in the species Homo sapiens

Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase, is an enzyme that in humans is encoded by the RPS6KB1 gene. It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. As the name suggests, its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome.

<span class="mw-page-title-main">Protein kinase, AMP-activated, alpha 1</span> Protein-coding gene in the species Homo sapiens

5'-AMP-activated protein kinase catalytic subunit alpha-1 is an enzyme that in humans is encoded by the PRKAA1 gene.

<span class="mw-page-title-main">TANK-binding kinase 1</span> Protein-coding gene in the species Homo sapiens

TBK1 is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase. It is encoded by the TBK1 gene in humans. This kinase is mainly known for its role in innate immunity antiviral response. However, TBK1 also regulates cell proliferation, apoptosis, autophagy, and anti-tumor immunity. Insufficient regulation of TBK1 activity leads to autoimmune, neurodegenerative diseases or tumorigenesis.

<span class="mw-page-title-main">RPS6KA2</span> Enzyme found in humans

Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene.

<span class="mw-page-title-main">MARK1</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase MARK1 is an enzyme that in humans is encoded by the MARK1 gene.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

<span class="mw-page-title-main">Protein phosphorylation</span> Process of introducing a phosphate group on to a protein

Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become activated, deactivated, or otherwise modifying its function. Approximately 13,000 human proteins have sites that are phosphorylated.

<span class="mw-page-title-main">STK24</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase 24 is an enzyme that in humans is encoded by the STK24 gene located in the chromosome 13, band q32.2. It is also known as Mammalian STE20-like protein kinase 3 (MST-3). The protein is 443 amino acids long and its mass is 49 kDa.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

Tuberous sclerosis proteins 1 and 2, also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The encoding two genes are TSC1 and TSC2. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. Depending on the grade of the disease, intellectual disability, epilepsy and tumors of the skin, retina, heart, kidney and the central nervous system can be symptoms.

AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in S.cerevisiae, encoded by the gene ATG1. It is essential for the initial building of the autophagosome and Cvt vesicles. In a non-kinase role it is - through complex formation with Atg13 and Atg17 - directly controlled by the TOR kinase, a sensor for nutrient availability.

<span class="mw-page-title-main">Autophagy-related protein 13</span> Protein-coding gene in the species Homo sapiens

Autophagy-related protein 13 also known as ATG13 is a protein that in humans is encoded by the KIAA0652 gene.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000177169 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029512 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T, et al. (July 1998). "Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment". Genomics. 51 (1): 76–85. doi:10.1006/geno.1998.5340. PMID   9693035.
  6. ↑ "Entrez Gene: ULK1 unc-51-like kinase 1 (C. elegans)".
  7. ↑ Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T, Muramatsu M, Shirasawa T (Jul 1998). "Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment". Genomics. 51 (1): 76–85. doi:10.1006/geno.1998.5340. PMID   9693035.[ verification needed ]
  8. ↑ "Entrez Gene: ULK1 unc-51-like kinase 1 (C. elegans)".[ verification needed ]
  9. ↑ Ro SH, Jung CH, Hahn WS, Xu X, Kim YM, Yun YS, et al. (December 2013). "Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes". Autophagy. 9 (12): 2103–2114. doi:10.4161/auto.26563. PMC   4028344 . PMID   24135897.
  10. 1 2 3 Lin MG, Hurley JH (April 2016). "Structure and function of the ULK1 complex in autophagy". Current Opinion in Cell Biology. 39: 61–68. doi:10.1016/j.ceb.2016.02.010. PMC   4828305 . PMID   26921696.
  11. 1 2 Lazarus MB, Novotny CJ, Shokat KM (January 2015). "Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors". ACS Chemical Biology. 10 (1): 257–261. doi:10.1021/cb500835z. PMC   4301081 . PMID   25551253.
  12. ↑ Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. (July 2013). "ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase". Nature Cell Biology. 15 (7): 741–750. doi:10.1038/ncb2757. PMC   3885611 . PMID   23685627.
  13. ↑ Kim J, Kundu M, Viollet B, Guan KL (February 2011). "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1". Nature Cell Biology. 13 (2): 132–141. doi:10.1038/ncb2152. PMC   3987946 . PMID   21258367.
  14. ↑ Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, et al. (2015). "Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates". PLOS Genetics. 11 (2): e1004987. doi: 10.1371/journal.pgen.1004987 . PMC   4344198 . PMID   25723488.
  15. 1 2 Okazaki N, Yan J, Yuasa S, Ueno T, Kominami E, Masuho Y, et al. (December 2000). "Interaction of the Unc-51-like kinase and microtubule-associated protein light chain 3 related proteins in the brain: possible role of vesicular transport in axonal elongation". Brain Research. Molecular Brain Research. 85 (1–2): 1–12. doi:10.1016/s0169-328x(00)00218-7. PMID   11146101.
  16. ↑ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi: 10.1038/msb4100134 . PMC   1847948 . PMID   17353931. 89.
  17. 1 2 Tomoda T, Kim JH, Zhan C, Hatten ME (March 2004). "Role of Unc51.1 and its binding partners in CNS axon outgrowth". Genes & Development. 18 (5): 541–558. doi: 10.1101/gad.1151204 . PMC   374236 . PMID   15014045.
  18. ↑ Kim J, Kundu M, Viollet B, Guan KL (February 2011). "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1". Nature Cell Biology. 13 (2): 132–141. doi:10.1038/ncb2152. PMC   3987946 . PMID   21258367.
  19. ↑ Xie Y, Kang R, Sun X, Zhong M, Huang J, Klionsky DJ, Tang D (2015-01-02). "Posttranslational modification of autophagy-related proteins in macroautophagy". Autophagy. 11 (1): 28–45. doi:10.4161/15548627.2014.984267. PMC   4502723 . PMID   25484070.
  20. ↑ Mohamud Y, Shi J, Tang H, Xiang P, Xue YC, Liu H, et al. (November 2020). "Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes". Scientific Reports. 10 (1): 19068. doi: 10.1038/s41598-020-76227-7 . PMC   7642411 . PMID   33149253.
  21. ↑ Chen MB, Ji XZ, Liu YY, Zeng P, Xu XY, Ma R, et al. (May 2017). "Ulk1 over-expression in human gastric cancer is correlated with patients' T classification and cancer relapse". Oncotarget. 8 (20): 33704–33712. doi:10.18632/oncotarget.16734. PMC   5464904 . PMID   28410240.
  22. ↑ Lee KM, Hwang SK, Lee JA (September 2013). "Neuronal autophagy and neurodevelopmental disorders". Experimental Neurobiology. 22 (3): 133–142. doi:10.5607/en.2013.22.3.133. PMC   3807000 . PMID   24167408.
  23. ↑ Henckaerts L, Cleynen I, Brinar M, John JM, Van Steen K, Rutgeerts P, Vermeire S (June 2011). "Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease". Inflammatory Bowel Diseases. 17 (6): 1392–1397. doi: 10.1002/ibd.21486 . PMID   21560199. S2CID   44342825.
  24. ↑ Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, et al. (July 2015). "Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates". Molecular Cell. 59 (2): 285–297. doi:10.1016/j.molcel.2015.05.031. PMC   4530630 . PMID   26118643.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.