Target of rapamycin complex subunit LST8

UniProt Q9BVC4 Organism Homo sapiens Gene GBL, LST8, MLST8

Also known as: GBL, LST8, MLST8

Function

Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. In response to nutrients, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating several substrates, such as ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1). In the same time, it inhibits catabolic pathways by phosphorylating the autophagy initiation components ULK1 and ATG13, as well as transcription factor TFEB, a master regulators of lysosomal biogenesis and autophagy. The mTORC1 complex is inhibited in response to starvation and amino acid depletion. Within mTORC1, MLST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. As part of the mTORC2 complex, transduces signals from growth factors to pathways involved in proliferation, cytoskeletal organization, lipogenesis and anabolic output. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. In response to growth factors, mTORC2 phosphorylates and activates AGC protein kinase family members, including AKT (AKT1, AKT2 and AKT3), PKC (PRKCA, PRKCB and PRKCE) and SGK1. mTORC2 functions upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 activation by mediating phosphorylation of different sites depending on the context, such as 'Thr-450', 'Ser-473', 'Ser-477' or 'Thr-479', facilitating the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDPK1/PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MLST8 acts as a bridge between MAPKAP1/SIN1 and MTOR.

Classification

Family (Pfam): PF00400 WD40
InterPro: MLST8, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf, WD40_PAC1, WD40_repeat_CS, WD40_rpt
Functional cluster: S-Adenosylmethionine Synthases & related

Experimental structures · PDB · 36

4JSN X-ray 3.20A
4JSP X-ray 3.30A
4JSV X-ray 3.50A
4JSX X-ray 3.50A
4JT5 X-ray 3.45A
4JT6 X-ray 3.60A
5FLC EM 5.90A
5H64 EM 4.40A
5WBU X-ray 3.42A
5WBY X-ray 3.10A
5ZCS EM 4.90A
6BCU EM 3.43A
… and 24 more

A predicted model is available from AlphaFold.

Gene Ontology · 24

Drugs targeting this protein · 1

INDOXIMOD activator

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Serine/threonine-protein kinase mTOR 19 shared papers
Target of rapamycin complex subunit LST8 3 shared papers
Rapamycin-insensitive companion of mTOR 9 shared papers
Proline-rich AKT1 substrate 1 3 shared papers
Regulatory-associated protein of mTOR 10 shared papers
Target of rapamycin complex 2 subunit MAPKAP1 6 shared papers
Proline-rich protein 5 2 shared papers
GTP-binding protein Rheb 2 shared papers
Sodium-coupled neutral amino acid transporter 7 1 shared papers
DEP domain-containing mTOR-interacting protein 3 shared papers
Proline-rich protein 5-like 1 shared papers
Eukaryotic translation initiation factor 4E-binding protein 1 3 shared papers

Literature · 34 cited papers

SUMO modifies GbetaL and mediates mTOR signaling. J. Biol. Chem. · 2024
Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. Nature · 2023
Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt. J. Biol. Chem. · 2022
SNAT7 regulates mTORC1 via macropinocytosis. Proc. Natl. Acad. Sci. U.S.A. · 2022
CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma. Cancer Sci. · 2022
Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace. Elife · 2021
Regulation of human mTOR complexes by DEPTOR. Elife · 2021
The 3.2-Aa resolution structure of human mTORC2. Sci. Adv. · 2020
Architecture of human Rag GTPase heterodimers and their complex with mTORC1. Science · 2019
Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo. Cancer Res. · 2019
The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Sci. Transl. Med. · 2018
Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration. Sci. Adv. · 2018
… and 22 more in the literature graph

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