Systematic analysis of the effects of splicing on the diversity of post-translational modifications in protein isoforms using PTM-POSE
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Abstract
Post-translational modifications (PTMs) and splicing are both important regulatory processes controlling protein function; therefore, we developed PTM-POSE (PTM projection onto splice events) to explore the interplay between them. PTM-POSE identifies potential PTM sites associated with alternative isoforms or splice events, enabling comprehensive analysis of how PTMs affect isoform function, protein interactions, and enzymatic regulation. Through systematic analysis of Ensembl transcripts with PTM-POSE, we highlighted two key mechanisms by which splicing diversifies PTMs across isoforms-exclusion of a PTM site (32%) or alteration of the flanking sequences surrounding the PTM (2%). In experiment-specific analysis of PTM-associated splicing events, we identified the potential rewiring of protein-interaction and kinase-substrate networks, suggesting coordinated connections between PTM signaling. We provide our tool and associated data publicly to enable further exploration of splicing-PTM relationships. A record of this paper's transparent peer review process is included in the supplemental information.
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Alternative splicing and post-translational modifications significantly amplify the molecular diversity of synapses, allowing a single gene to produce multiple protein isoforms with distinct functions and regulatory properties.
“Beyond the sheer number of genes encoding synaptic proteins, alternative splicing and post-translational modifications (PTMs) significantly amplify the molecular diversity of synapses, allowing a single gene to produce multiple protein isoforms (proteoforms) with distinct functions and regulatory properties [87].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [87]
The Introduction says alternative splicing and PTMs generate proteoforms with distinct functions, and gives a neuroligin-1 example affecting synapse formation. The Results describe isoform-specific PTM availability and potential regulatory interactions. The paper does not establish that these mechanisms significantly amplify the molecular diversity of synapses as a whole. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPost-translational modifications such as phosphorylation, palmitoylation, and glycosylation further diversify the proteome by altering protein function, stability, localization, and interaction partners.
“Post-translational modifications (PTMs), such as phosphorylation, palmitoylation, and glycosylation, further diversify the proteome by altering protein function, stability, localization, and interaction partners [5,87].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [87]
The Introduction describes PTMs as a source of functionally distinct proteoforms, and the Results section on PTM inclusion links PTM sites to protein activity, intracellular localization, and molecular associations. The paper also discusses phosphorylation, palmitoylation, and glycosylation as PTM types. The cited passages do not support the specific claim that PTMs alter protein stability. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlternative splicing and post-translational modifications are known to generate immense synaptic protein diversity.
“Although alternative splicing and post-translational modifications are known to generate immense synaptic protein diversity, a detailed understanding of how these modifications precisely rewire protein interaction and regulatory networks in specific biological contexts is still emerging [87].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [87]
The Introduction (page unavailable) says alternative splicing and PTMs generate distinct protein forms and gives a neuroligin-1 example affecting synapse formation. It does not establish that these mechanisms generate immense diversity specifically among synaptic proteins; its broader analysis concerns the human proteome. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA smaller but notable percentage of PTM sites exhibit altered regulatory sequences surrounding the modification site, suggesting changes in binding interactions.
“Recent computational analyses have shown that a significant percentage of PTM sites are excluded from at least one protein isoform due to alternative splicing, and a smaller but notable percentage exhibit altered regulatory sequences surrounding the modification site, suggesting changes in binding interactions [87].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [87]
A significant percentage of PTM sites are excluded from at least one protein isoform due to alternative splicing.
“Recent computational analyses have shown that a significant percentage of PTM sites are excluded from at least one protein isoform due to alternative splicing, and a smaller but notable percentage exhibit altered regulatory sequences surrounding the modification site, suggesting changes in binding interactions [87].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [87]
A detailed understanding of how alternative splicing and PTMs precisely rewire protein interaction and regulatory networks in specific biological contexts is still emerging.
“Although alternative splicing and post-translational modifications are known to generate immense synaptic protein diversity, a detailed understanding of how these modifications precisely rewire protein interaction and regulatory networks in specific biological contexts is still emerging [87].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [87]
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Ghadie, M. A., Lambourne, L., Vidal, M., & Xia, Y. (2017) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1005717 · Cited by 39 · see citing works
Louadi, Z., Elkjaer, M. L., Klug, M., Lio, C. T., Fenn, A. M., Illés, Z., Bongiovanni, D., Baumbach, J., Kacprowski, T., List, M., et al. (2021) · Genome biology · doi:10.1186/s13059-021-02538-1 · Cited by 34 · see citing works
KSTAR: An algorithm to predict patient-specific kinase activities from phosphoproteomic data
Crowl, S., Jordan, B. T., Ahmed, H., Ma, C. X., & Naegle, K. M. (2022) · Nature Communications · doi:10.1038/s41467-022-32017-5 · Cited by 34 · see citing works
Self-citationPillmann, H., Hatje, K., Odronitz, F., Hammesfahr, B., & Kollmar, M. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-270 · Cited by 30 · see citing works
Agosto, L. M., Gazzara, M. R., Radens, C. M., Sidoli, S., Baeza, J., Garcia, B. A., & Lynch, K. W. (2019) · Genome Research · doi:10.1101/gr.248435.119 · Cited by 28 · see citing works
Underlying mechanisms of epithelial splicing regulatory proteins in cancer progression
Liu, Y., Li, Y., Du, C., Kuang, S., Zhou, X., Zhang, J., & Ao, X. (2022) · Journal of Molecular Medicine · doi:10.1007/s00109-022-02257-5 · Cited by 28 · see citing works
Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1
Lo, A., Holmes, K., Kamlapurkar, S., Mundt, F., Moorthi, S., Fung, I., Fereshetian, S., Watson, J., Carr, S. A., Mertins, P., et al. (2021) · Science Signaling · doi:10.1126/scisignal.abc4520 · Cited by 21 · see citing works
Freytag, M., Kluth, M., Bady, E., Hube‐Magg, C., Makrypidi‐Fraune, G., Hans Heinzer, A., Höflmayer, D., Weidemann, S. A., Uhlig, R., Huland, H., et al. (2020) · BMC Cancer · doi:10.1186/s12885-020-07682-8 · Cited by 21 · see citing works
Low, Z. Y., Yip, A. J. W., Chan, A. M. L., & Choo, W. S. (2024) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30624 · Cited by 19 · see citing works
A highly multiplexed quantitative phosphosite assay for biology and preclinical studies
Keshishian, H., McDonald, E. R., Mundt, F., Melanson, R., Krug, K., PORTER, D. A., Wallace, L., Forestier, D., Rabasha, B., Marlow, S., et al. (2021) · Molecular Systems Biology · doi:10.15252/msb.202010156 · Cited by 17 · see citing works
Oncogenic KRAS alters splicing factor phosphorylation and alternative splicing in lung cancer
Lo, A., McSharry, M. V., & Berger, A. H. (2022) · BMC Cancer · doi:10.1186/s12885-022-10311-1 · Cited by 16 · see citing works
Antisense suppression of donor splice site mutations in the dystrophin gene transcript
Fletcher, S., Meloni, P. L., Johnsen, R. D., Wong, B. L. Y., Muntoni, F., & Wilton, S. D. (2013) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.19 · Cited by 14 · see citing works
Correction: A Dynamic View of Domain-Motif Interactions
Akiva, E., Friedlander, G., Barnett‐Itzhaki, Z., & Margalit, H. (2012) · PLoS Computational Biology · doi:10.1371/annotation/2e21b1b9-46de-4cbe-a2a4-b4598d90d492 · Cited by 14 · see citing works
Dakup, P., Feng, S., Shi, T., Jacobs, J., Wiley, H. S., & Qian, W. (2023) · Molecules · doi:10.3390/molecules28031143 · Cited by 11 · see citing works
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Characterizing alternative splicing effects on protein interaction networks with LINDA
Gjerga, E., Vries, I. S. N., & Dieterich, C. (2023) · Bioinformatics · doi:10.1093/bioinformatics/btad224 · Cited by 10 · see citing works
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The pandas development team (2024) · Zenodo · doi:10.5281/zenodo.13819579
Flagged first, then by citations
1 of the 100 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The role of molecular chaperone CCT/TRiC in translation elongation: A literature review
Que, Y., Qiu, Y., Ding, Z., Zhang, S., Wei, R., Xia, J., & Lin, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e29029 · Cited by 12 · see citing works
Molecular Physiology of the Neuronal Synapse
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Lehe, M. D., Almofeez, R., Jeffery, E. D., & Sheynkman, G. (2026) · Journal of Mass Spectrometry · doi:10.1002/jms.70024 · Cited by 3 · see citing works
Alatawi, S. M. (2026) · Clinical & Translational Oncology · doi:10.1007/s12094-025-04217-0 · Cited by 1 · see citing works
IsoProDB: an integrated map of human protein isoforms for accelerated research
Soman, S. P., Ummar, S., Ahmed, M., Shivamurthy, P. B., Sreelan, S., Ramesh, P., Nisar, M., Subbannayya, Y., & Raju, R. (2026) · Database · doi:10.1093/database/baag015 · Cited by 1 · see citing works
SpliceImpactR maps alternative RNA processing events driving protein functional diversity
Wakefield, Z. P., & Fiszbein, A. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag827 · Cited by 1 · see citing works
Evaluating splicing factor and kinase network crosstalk through global phosphoproteomicsPreprint
Crowl, S., Singh, S., Zhang, T., & Naegle, K. M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.16.718710
Self-citationShen, Y., Mao, Z., Zhang, X., Yang, Y., Shen, Z., He, H., Chen, C., & Liu, J. (2026) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2026.1769113
Matricellular Proteins in Bladder Cancer: Context-Dependent Roles in Tumor Promotion and Suppression
Akhmetkaliyev, A., García, J. H. G. F., Sonnenberg-Riethmacher, E., & Riethmacher, D. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27156807
- Authors
- Crowl, S., Coleman, M. B., Chaphiv, A., Jordan, B. T., & Naegle, K. M.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Crowl, Sam
- Naegle, Kristen M.
- Venue
- Cell Systems
- Publisher
- Elsevier BV
- Published
- 2025-07
- Volume
- 16
- Issue
- 7
- Pages
- 101318
- ISSN
- 2405-4712 (ISSN-L)
- PMC
- PMC12226790
- OpenAlex
- W4411237912
- Cited by
- 10
- References
- 100
- Citations by year
- 2026: 8 · 2025: 1 · 2024: 1
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 380 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Systems (acceptedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- NIH National Institute of General Medical Sciences (R35GM138127)
- National Science Foundation Graduate Research Fellowship Program (1842490)
- National Science Foundation
- National Institutes of Health
- University of Virginia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- post-translational modification, alternative splicing, protein isoforms, protein-protein interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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