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SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Gao, Jie 
Sidiropoulou, Eirini 
Walker, Ieuan 
Mizielinski, Karol 

Abstract

Serum and glucocorticoid-regulated kinase 1 (SGK1) is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL). However, little is known about its function or the consequence of its mutation. The frequent finding of truncating mutations has led to the widespread assumption that these represent loss-of-function variants and, accordingly, that SGK1 must act as a tumor suppressor. In this study, instead, the most common SGK1 mutations led to production of aberrantly spliced messenger RNA neoisoforms in which translation is initiated from downstream methionines. The resulting N-terminal truncated protein isoforms showed increased expression related to the exclusion of an N-terminal degradation domain. However, they retained a functional kinase domain, the overexpression of which rendered cells resistant to AKT inhibition, in part because of increased phosphorylation of GSK3B. These findings challenge the prevailing assumption that SGK1 is a tumor-suppressor gene in DLBCL and provide the impetus to explore further the pharmacological inhibition of SGK1 as a therapeutic strategy for DLBCL.

Description

Keywords

Cells, Cultured, Enzyme Stability, Humans, Immediate-Early Proteins, Lymphoma, Large B-Cell, Diffuse, Phosphorylation, Protein Domains, Protein Isoforms, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt

Journal Title

Blood

Conference Name

Journal ISSN

0006-4971
1528-0020

Volume Title

138

Publisher

American Society of Hematology

Rights

All rights reserved
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (A25117)
Medical Research Council (MR/M008584/1)
MRC (MC_UU_12022/10)
Medical Research Council (MC_PC_17230)
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