DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3β to downregulate β-catenin transcription target, osteopontin
Open accessAbstract
Elevated levels of the oncoprotein, osteopontin (OPN), are associated with poor outcome of several types of cancers including melanoma. We have previously reported an important involvement of DNAJB6, a member of heat-shock protein 40 (HSP40) family, in negatively impacting tumor growth. The current study was prompted by our observations reported here which revealed a reciprocal relationship between DNAJB6 and OPN in melanoma specimens. The 'J domain' is the most conserved domain of HSP40 family of proteins. Hence, we assessed the functional role of the J domain in activities of DNAJB6. We report that the J domain of DNAJB6 is involved in mediating OPN suppression. Deletion of the J domain renders DNAJB6 incapable of impeding malignancy and suppressing OPN. Our mechanistic investigations reveal that DNAJB6 binds HSPA8 (heat-shock cognate protein, HSC70) and causes dephosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser 9 by recruiting protein phosphatase, PP2A. This dephosphorylation activates GSK3β, leading to degradation of β-catenin and subsequent loss of TCF/LEF (T cell factor1/lymphoid enhancer factor1) activity. Deletion of the J domain abrogates assembly of this multiprotein complex and renders GSK3β inactive, thus, stabilizing β-catenin, a transcription co-activator for OPN expression. Our in-vitro and in-vivo functional analyses show that silencing OPN expression in the background of deletion of the J domain renders the resultant tumor cells less malignant despite the presence of stabilized β-catenin. Thus, we have uncovered a new mechanism for regulation of GSK3β activity leading to inhibition of Wnt/β-catenin signaling.
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PP2A has been shown to regulate GSK3β activity by removing phosphorylation at serine 9 and other regulatory residues.
“PP2A has been shown to regulate GSK3 b activity by removing phosphorylation at serine 9 and other regulatory residues (Bennecib et al., 2000; Mitra et al., 2012).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Mitra et al., 2012
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- Authors
- Mitra, A., Menezes, M. E., Pannell, L. K., Mulekar, M. S., Honkanen, R. E., Shevde, L. A., & Samant, R. S.
- Affiliations
- USA Mitchell Cancer Institute (US)
- University of South Alabama (US)
- Corresponding author
- Samant, R S
- Venue
- Oncogene
- Published
- 2012-01-23
- Volume
- 31
- Issue
- 41
- Pages
- 4472-4483
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3717376
- OpenAlex
- W1977450402
- Cited by
- 64
- References
- 75
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 1 · 2021: 7 · 2020: 5 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 1 · 2013: 3 · 2012: 3
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service
- National Cancer Institute (CA140472, CA138850, R01CA140472, R01CA060750, R01CA138850)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- DNAJB6, osteopontin, melanoma, protein phosphatase 2A, β-catenin degradation, Wnt/β-catenin signaling, TCF/LEF transcription, Hsc70, tumor suppression, molecular chaperones
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Female, Humans, Melanoma, Mice, Nude, Neoplasm Transplantation, Nerve Tissue Proteins, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Skin Neoplasms, Transcription, Genetic, Down-Regulation, Gene Expression Regulation, Neoplastic, Protein Structure, Tertiary, Molecular Chaperones, Okadaic Acid, Oligonucleotide Array Sequence Analysis, Glycogen Synthase Kinase 3, Cell Line, Tumor, HSC70 Heat-Shock Proteins, HSP40 Heat-Shock Proteins, beta Catenin, Mice, Lymphoid Enhancer-Binding Factor 1, T Cell Transcription Factor 1, Osteopontin, Protein Phosphatase 2, Protein Interaction Domains and Motifs, Epithelial-Mesenchymal Transition, Transcriptome
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