title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
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").
authors.affiliation: Genomic 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.
authors.forename: Xinping
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Bioengineering, McGill University, Montreal, QC H3A 0C3, Canada.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Coulombe-Huntington
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shuli
authors.initials: S
authors.lastname: Kang
authors.affiliation: Genomic 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.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Sheynkman
authors.affiliation: Genomic 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.
authors.forename: Tong
authors.initials: T
authors.lastname: Hao
authors.affiliation: Genomic 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.
authors.forename: Aaron
authors.initials: A
authors.lastname: Richardson
authors.affiliation: 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; Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.
authors.forename: Song
authors.initials: S
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Genomic 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.
authors.forename: Yun A
authors.initials: YA
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Murray
authors.affiliation: Genomic 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.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Spirohn
authors.affiliation: Genomic 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.
authors.forename: Bridget E
authors.initials: BE
authors.lastname: Begg
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Catalonia, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Duran-Frigola
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: MacWilliams
authors.affiliation: 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 Biomedical Engineering, Boston University, Boston, MA 02215, USA; Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pevzner
authors.affiliation: 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.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: 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.
authors.forename: Shelly A
authors.initials: SA
authors.lastname: Wanamaker
authors.affiliation: 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.
authors.forename: Stanley
authors.initials: S
authors.lastname: Tam
authors.affiliation: 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.
authors.forename: Lila
authors.initials: L
authors.lastname: Ghamsari
authors.affiliation: Genomic 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.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Genomic 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.
authors.forename: Song
authors.initials: S
authors.lastname: Yi
authors.affiliation: 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.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Rodriguez
authors.affiliation: Genomic 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.
authors.forename: Dawit
authors.initials: D
authors.lastname: Balcha
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Guihong
authors.initials: G
authors.lastname: Tan
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Brenda
authors.initials: B
authors.lastname: Andrews
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.affiliation: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Xianghong J
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Salehi-Ashtiani
authors.affiliation: Genomic 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.
authors.forename: Benoit
authors.initials: B
authors.lastname: Charloteaux
authors.affiliation: Genomic 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.
authors.forename: Alyce A
authors.initials: AA
authors.lastname: Chen
authors.affiliation: Genomic 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Calderwood
authors.affiliation: Institute 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aloy
authors.affiliation: Genomic 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.
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
authors.affiliation: Genomic 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.
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lilyak@ucsd.edu.
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
authors.affiliation: Center 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Genomic 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D016366:Open Reading Frames; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000378:metabolism*; D020543:Proteome / Q000032:analysis / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D020543:Proteome