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The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI.
- Source :
-
Cell reports [Cell Rep] 2017 Sep 05; Vol. 20 (10), pp. 2468-2479. - Publication Year :
- 2017
-
Abstract
- The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention.<br /> (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Autophagy physiology
Female
Fluorescent Antibody Technique
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism
Mice
Protein Serine-Threonine Kinases genetics
Signal Transduction genetics
Zinc Finger Protein GLI1 genetics
Cancer-Associated Fibroblasts metabolism
Fibroblasts metabolism
Protein Serine-Threonine Kinases metabolism
Signal Transduction physiology
Zinc Finger Protein GLI1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 20
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 28877478
- Full Text :
- https://doi.org/10.1016/j.celrep.2017.08.048