title: Construction and analysis of a human testis/sperm-enriched interaction network: Unraveling the PPP1CC2 interactome.
abstract: Phosphoprotein phosphatase 1 catalytic subunit gamma 2 (PPP1CC2), a PPP1CC tissue-specific alternative splice restricted to testicular germ cells and spermatozoa, is essential for spermatogenesis and spermatozoa motility. The key to understand PPP1CC2 regulation lies on the characterization of its interacting partners.
  
  
  
  We construct a testis/sperm-enriched protein interaction network and analyzed the topological properties and biological context of the network. Further the interaction of a potential target for pharmacological intervention was validated in human spermatozoa.
  
  
  
  A total of 1778 proteins and 32,187 interactions between them were identified in the testis/sperm-enriched network. The network analysis revealed the members of functional modules that interact more tightly with each other. In the network, PPP1CC was located in the fourth maximum core part (k=41) and had 106 direct interactors. Sixteen PPP1CC interactors were involved in spermatogenesis-related categories. Also, PPP1CC had 50 direct interactors, highly interconnected and many of them part of the network maximum core (k=44), associated with motility-related annotations, including several previously uncharacterized interactors, such as, LMNA, JAK2 and RIPK3.
  
  
  
  In this study we integrated tissue-specific protein expression and protein-protein interaction data in order to identify key PPP1CC2 complexes for male reproductive functions. One of the most intriguing interactors was A-kinase anchor protein 4 (AKAP4), a testis-specific protein related to infertility phenotypes and involved in all major motility-related annotations.
  
  
  
  We demonstrated for the first time the interaction between PPP1CC2 and AKAP4 in human spermatozoa and the potential of the complex as contraceptive target.
authors.affiliation: Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Joana Vieira
authors.initials: JV
authors.lastname: Silva
authors.affiliation: Physics Department, I3N, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: De Bock
authors.affiliation: Physics Department, I3N, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Goltsev
authors.affiliation: Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium; Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Physics Department, I3N, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: José Fernando F
authors.initials: JF
authors.lastname: Mendes
authors.affiliation: Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal. Electronic address: mfardilha@ua.pt.
authors.forename: Margarida
authors.initials: M
authors.lastname: Fardilha
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007246:Infertility / Q000378:metabolism / Q000473:pathology; D053614:Janus Kinase 2 / Q000378:metabolism; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D060066:Protein Interaction Maps / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013081:Sperm Motility / Q000502:physiology; D013091:Spermatogenesis / Q000502:physiology; D013094:Spermatozoa / Q000378:metabolism*; D013737:Testis / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C485480:AKAP4 protein, human; D004268:DNA-Binding Proteins; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; C110225:PPP1R10 protein, human; D016601:RNA-Binding Proteins; D053614:Janus Kinase 2; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Phosphoprotein phosphatase 1; Protein-protein interaction network; Spermatozoa; Testis