ArticleCell2016
Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
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Article in Cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 359 papers.
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359citing papers in PubMed
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359 citing papers in PubMed.
- Alternative splicing fine-tunes modular protein interfaces to control protein localization.Nature structural & molecular biology · 2026Article
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- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- Nanopore long-read transcriptome sequencing reveals miR-22-3p-mediated transcriptomic remodeling and alternative splicing in chicken pectoral muscle.Poultry science · 2026Article
- Large-scale single-molecule analysis of tau proteoforms.Nature methods · 2026Article
- Peroxisomal interactome mapping enables network-based modelling of function and disease.Life science alliance · 2026Article
- SpliceImpactR maps alternative RNA processing events driving protein functional diversity.Nucleic acids research · 2026Article
- Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.Genes & development · 2026Article
- Tools and tactics for studying alternative splicing.Nature reviews. Genetics · 2026Review
- Transcriptomic Analysis Reveals Multilayer Regulation Underlying Development and Pregnancy in the Malayan Pangolin.Animal genetics · 2026Article
- Alternative splicing in layer 3 pyramidal neurons differs across regions of the human cortical hierarchy.Cerebral cortex (New York, N.Y. : 1991) · 2026Article
- Matricellular Proteins in Bladder Cancer: Context-Dependent Roles in Tumor Promotion and Suppression.International journal of molecular sciences · 2026Review
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- Subcellular localization as a driver of protein function.Nature reviews. Molecular cell biology · 2026Review
- Chimeric antigen receptor T cell targeting CD44E variant in HCC holds therapeutic potential.Molecular therapy. Oncology · 2026Article
- Disease-associated genetic variants can cause missense effects in tissue-specific protein isoforms.Nature communications · 2026Article
- Leveraging nanoparticle protein corona to advance plasma proteome profiling.Nature communications · 2026Review
- Integrated top-down and bottom-up proteomics enables precise characterization of proteoforms within the protein corona.Nature communications · 2026Article
- IsoPepTracker: An interactive web application for peptide-driven isoform analysis.PLoS computational biology · 2026Article
299 more citing papers are in PubMed but not listed here.
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Authors and funding
38 authors.
Xinping YangGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Jasmin Coulombe-HuntingtonDepartment of Bioengineering, McGill University, Montreal, QC H3A 0C3, Canada.
Shuli KangDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Gloria M SheynkmanGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Tong HaoGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Aaron RichardsonGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Song SunDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.
Fan YangDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Yun A ShenGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Ryan R MurrayCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Kerstin SpirohnGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Bridget E BeggGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Miquel Duran-FrigolaInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain.
Andrew MacWilliamsCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Samuel J PevznerCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Boston University School of Medicine, Boston, MA 02118, USA.
Quan ZhongCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Shelly A WanamakerCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Stanley TamCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Lila GhamsariCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Nidhi SahniGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Song YiGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Maria D RodriguezCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Dawit BalchaGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Guihong TanDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Michael CostanzoDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Brenda AndrewsDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada.
Charles BooneDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada.
Xianghong J ZhouMolecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Kourosh Salehi-AshtianiCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Benoit CharloteauxGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Alyce A ChenGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Michael A CalderwoodGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Patrick AloyInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Catalonia, Spain.
Frederick P RothGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Canadian Institute for Advanced Research, Toronto, ON M5G 1Z8, Canada.
David E HillGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Lilia M IakouchevaDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lilyak@ucsd.edu.
Yu XiaCenter for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Bioengineering, McGill University, Montreal, QC H3A 0C3, Canada. Electronic address: brandon.xia@mcgill.ca.
Marc VidalGenomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marc_vidal@dfci.harvard.edu.
Funding
Genomic Analysis of Network Perturbations in Human DiseaseP50HG004233 · NHGRI · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2007 to 2017
$31.6MThe C. elegans Interactome ProjectR01HG001715 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI HILL, DAVID E., ROTH, FREDERICK P · 1998 to 2010
$16.5MTumor Cell Biology Training ProgramT32CA009361 · NCI · DANA-FARBER CANCER INSTITUTE · PI GRAY, NATHANAEL SCHIANDER · 1985 to 2015
$8.9MMapping the first half of the REFERENCE human binary protein interactomeU01HG001715 · NHGRI · DANA-FARBER CANCER INST · PI HILL, DAVID E., ROTH, FREDERICK P · 2012 to 2014
$5.4MResource ProjectU41HG001715 · NHGRI · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2015 to 2017
$4.7MSchizophrenia interactome mapping and global discovery of brain splice variantsR01MH091350 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAO, TONG, IAKOUCHEVA, LILIA M · 2010 to 2014
$2.9MApplication of Technologies for Interactome Network Analyses of Cancer MutationsR33CA132073 · NCI · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2008 to 2010
$1.8MA computational framework for predicting the impact of mutations in autismR01MH105524 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI IAKOUCHEVA, LILIA M, RADIVOJAC, PREDRAG · 2014 to 2016
$1.4MA systems biology approach to unravel theunderlying functional modules of ASDR01HD065288 · NICHD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI IAKOUCHEVA, LILIA M · 2009 to 2010
$1.3MIntegrative Analysis of Public RNA-seq RepositoriesR01GM105431 · NIGMS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZHOU, XIANGHONG JASMINE · 2013 to 2016
$1.3MProtein network of high risk copy number variants for psychiatric disordersR21MH104766 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI IAKOUCHEVA, LILIA M · 2014 to 2015
$421kNCI NIH HHS R33 CA132073NCI NIH HHS R33CA132073NCI NIH HHS T32 CA009361NCI NIH HHS T32CA009361NHGRI NIH HHS P50 HG004233NHGRI NIH HHS P50HG004233NHGRI NIH HHS R01 HG001715NHGRI NIH HHS U01 HG001715NHGRI NIH HHS U01HG001715NHGRI NIH HHS U41 HG001715NICHD NIH HHS R01 HD065288NICHD NIH HHS R01HD065288NIGMS NIH HHS R01 GM105431NIGMS NIH HHS R01GM105431NIMH NIH HHS R01 MH091350NIMH NIH HHS R01MH091350NIMH NIH HHS R01 MH105524NIMH NIH HHS R01MH105524NIMH NIH HHS R21 MH104766NIMH NIH HHS R21MH104766
Abstract
While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms" are functionally divergent (i.e., "functional alloforms").
Indexed as
Alternative SplicingAnimalsCloning, MolecularEvolution, MolecularHumansModels, MolecularOpen Reading FramesProtein Interaction Domains and MotifsProtein Interaction MapsProtein IsoformsProteomeProtein IsoformsProteome
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