In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 6 ( 2021-6-2), p. e3001281-
Abstract:
Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001281
DOI:
10.1371/journal.pbio.3001281.g001
DOI:
10.1371/journal.pbio.3001281.g002
DOI:
10.1371/journal.pbio.3001281.g003
DOI:
10.1371/journal.pbio.3001281.g004
DOI:
10.1371/journal.pbio.3001281.g005
DOI:
10.1371/journal.pbio.3001281.g006
DOI:
10.1371/journal.pbio.3001281.g007
DOI:
10.1371/journal.pbio.3001281.g008
DOI:
10.1371/journal.pbio.3001281.s001
DOI:
10.1371/journal.pbio.3001281.s002
DOI:
10.1371/journal.pbio.3001281.s003
DOI:
10.1371/journal.pbio.3001281.s004
DOI:
10.1371/journal.pbio.3001281.s005
DOI:
10.1371/journal.pbio.3001281.s006
DOI:
10.1371/journal.pbio.3001281.s007
DOI:
10.1371/journal.pbio.3001281.s008
DOI:
10.1371/journal.pbio.3001281.s009
DOI:
10.1371/journal.pbio.3001281.s010
DOI:
10.1371/journal.pbio.3001281.s011
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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