The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase
Open accessAbstract
Bone morphogenetic proteins (BMPs) are members of the TGF-beta family that regulate cell proliferation, apoptosis, and differentiation, and participate in the development of most tissues and organs in vertebrates. Smad proteins function downstream of TGF-beta receptor serine/threonine kinases and undergo serine phosphorylation in response to receptor activation. Smad1 is regulated in this fashion by BMP receptors, and Smad2 and Smad3 by TGF-beta and activin receptors. Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro. Mutation of these carboxy-terminal serines prevents several Smad1 activation events, namely, Smad1 association with the related protein DPC4, accumulation in the nucleus, and gain of transcriptional activity. Similar carboxy-terminal serines in Smad2 are required for its phosphorylation and association with DPC4 in response to TGF-beta, indicating the generality of this process of Smad activation. As a direct physiological substrate of BMP receptors, Smad1 provides a link between receptor serine/threonine kinases and the nucleus.
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SMAD1 is typically activated through BMP receptor-mediated phosphorylation.
“While SMAD1 is typically activated through BMP receptor-mediated phosphorylation,63 we found that SMAD1 transcripts are increased after KRAS-EGFR combined treatment, suggesting that alternative transcriptional or epigenetic mechanisms contribute to its upregulation.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [63]
Cites
<i>DPC4</i> , A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1
Hahn, S. A., Schutte, M., Shamsul Hoque, A. T. M., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., et al. (1996) · Science · doi:10.1126/science.271.5247.350 · Cited by 2,337 · see citing works
Activation of Signalling by the Activin Receptor Complex
Attisano, L., Wrana, J. L., Montalvo, E., & Massagué, J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.3.1066 · Cited by 316 · see citing works
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Signal transduction of bone morphogenetic protein receptors
Nohe, A. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2003.08.011 · Cited by 514 · see citing works
Structural insights into BMP receptors: Specificity, activation and inhibition
Yadin, D., Knaus, P., & Mueller, T. D. (2016) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.11.005 · Cited by 221 · see citing works
Ramachandran, A., Vizán, P., Das, D., Chakravarty, P., Vogt, J., Rogers, K. W., Müller, P., Hinck, A. P., Sapkota, G. P., & Hill, C. S. (2018) · eLife · doi:10.7554/elife.31756 · Cited by 204 · see citing works
Sun, J., Ishii, M., Ting, M.-C., & Maxson, R. (2013) · Development · doi:10.1242/dev.085225 · Cited by 57 · see citing works
Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
Zhang, Y., Chen, J., She, Y., Fang, Z., Zhang, Y., Ruan, D., Guo, W., Liao, J., Zhou, W., Lao, J., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.10.010 · Cited by 23 · see citing works
“While SMAD1 is typically activated through BMP receptor-mediated phosphorylation, 63 we found that SMAD1 transcripts are increased after KRAS-EGFR combined treatment, suggesting that alternative transcriptional or epigenetic mechanisms contribute to its upregulation.”
- Authors
- Kretzschmar, M., Liu, F., Hata, A., Doody, J., & Massagué, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Rutgers, The State University of New Jersey (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1997-04-15
- Volume
- 11
- Issue
- 8
- Pages
- 984-995
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W1989722096
- Cited by
- 574
- References
- 2
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 9 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 10 · 2019: 5 · 2018: 14 · 2017: 3 · 2016: 6 · 2015: 20 · 2014: 11 · 2013: 17 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Jane Coffin Childs Memorial Fund for Medical Research
- Memorial Sloan-Kettering Cancer Center
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Genentech
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- Smad1, BMP receptors, bone morphogenetic proteins, TGF-beta signaling, Smad phosphorylation, serine phosphorylation, Smad2, SMAD4, transcriptional activation, Smad activation
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Cell Nucleus, DNA-Binding Proteins, Epithelial Cells, Lung, Mink, Molecular Sequence Data, Mutation, Phosphopeptides, Phosphorylation, Serine, Signal Transduction, Trans-Activators, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Growth Factor, COS Cells, Activin Receptors, Activin Receptors, Type I, Smad Proteins, Smad2 Protein, Bone Morphogenetic Protein Receptors, Type I, Bone Morphogenetic Protein Receptors, Type II
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