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Investigation of th...
Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965
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- Ahwazi, Danial (författare)
- University of Copenhagen
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- Neopane, Katyayanee (författare)
- Swiss Federal Institute of Technology
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- Markby, Greg R. (författare)
- University of Copenhagen
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- Kopietz, Franziska (författare)
- Lund University,Lunds universitet,Proteinfosforylering,Forskargrupper vid Lunds universitet,Protein Phosphorylation,Lund University Research Groups
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- Ovens, Ashley J. (författare)
- St. Vincent’s Institute of Medical Research,Australian Catholic University
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- Dall, Morten (författare)
- University of Copenhagen
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- Hassing, Anna S. (författare)
- University of Copenhagen
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- Gräsle, Pamina (författare)
- University of Copenhagen
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- Alshuweishi, Yazeed (författare)
- King Saud University
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- Treebak, Jonas T. (författare)
- University of Copenhagen
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- Salt, Ian P. (författare)
- University of Glasgow
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- Göransson, Olga (författare)
- Lund University,Lunds universitet,Proteinfosforylering,Forskargrupper vid Lunds universitet,Protein Phosphorylation,Lund University Research Groups
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- Zeqiraj, Elton (författare)
- University of Leeds
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- Scott, John W. (författare)
- St. Vincent’s Institute of Medical Research,Australian Catholic University,The Florey Institute of Neuroscience and Mental Health
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- Sakamoto, Kei (författare)
- University of Copenhagen
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(creator_code:org_t)
- 2021
- 2021
- Engelska 21 s.
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Ingår i: Biochemical Journal. - 0264-6021. ; 478:15, s. 2977-2997
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMP-activated protein kinase (AMPK) inhibitor relative to the widely used, but promiscuous inhibitor Compound C/ Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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Till lärosätets databas
- Av författaren/redakt...
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Ahwazi, Danial
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Neopane, Katyaya ...
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Markby, Greg R.
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Kopietz, Franzis ...
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Ovens, Ashley J.
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Dall, Morten
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visa fler...
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Hassing, Anna S.
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Gräsle, Pamina
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Alshuweishi, Yaz ...
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Treebak, Jonas T ...
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Salt, Ian P.
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Göransson, Olga
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Zeqiraj, Elton
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Scott, John W.
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Sakamoto, Kei
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
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Biochemical Jour ...
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Lunds universitet