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Amyloid precursor protein interaction network in human testis: sentinel proteins for male reproduction.

Silva JV, Yoon S, Domingues S, Guimarães S, Goltsev AV, da Cruz E Silva EF, Mendes JF, da Cruz E Silva OA, Fardilha M - BMC Bioinformatics (2015)

Bottom Line: Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood.We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses.Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Signal Transduction, Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, 3810-193, Aveiro, Portugal. joanavieirasilva@ua.pt.

ABSTRACT

Background: Amyloid precursor protein (APP) is widely recognized for playing a central role in Alzheimer's disease pathogenesis. Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood. APP is involved in several biological functions which might be potentially important for male fertility, such as cell adhesion, cell motility, signaling, and apoptosis. Furthermore, APP superfamily members are known to be associated with fertility. Knowledge on the protein networks of APP in human testis and spermatozoa will shed light on the function of APP in the male reproductive system.

Results: We performed a Yeast Two-Hybrid screen and a database search to study the interaction network of APP in human testis and sperm. To gain insights into the role of APP superfamily members in fertility, the study was extended to APP-like protein 2 (APLP2). We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses. We classified significant features related to the human male reproduction for the APP interacting proteins and identified modules of proteins with similar functional roles which may show cooperative behavior for male fertility.

Conclusions: The present work provides the first report on the APP interactome in human testis. Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

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Related in: MedlinePlus

APP protein-protein interaction networks. (a) Local APP/APLP2 network. Proteins with light orange (M1) and dark orange (M4) are mostly involved in G-protein coupled receptor protein signaling pathway (Biological Process; BP) and located at the plasma membrane (Cellular Component; CC). Proteins with light green (M2) and dark green (M3) are mostly involved in regulation of apoptosis (BP) and located at the cell surface (CC). (b) Subnetwork of APP interactors involved in cell adhesion (BP) extracted from the extended APP/APLP2 protein-protein interaction network. (c) Subnetwork of APP interactors involved in vesicle-mediated transport (BP) extracted from the extended network. Red colored nodes represent the proteins from the YTH screen. Blue colored nodes indicate interactors extracted from the DBs. Node size represents relative degree of the nodes and the other interactions of nodes are neglected for the sake of simplicity. Dashed lines represent the interactions revealed by the YTH screening in human testis and solid lines are interactions from DBs. (d) Subnetwork of APP interactors involved in G-protein-coupled singnal pathways.
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Fig3: APP protein-protein interaction networks. (a) Local APP/APLP2 network. Proteins with light orange (M1) and dark orange (M4) are mostly involved in G-protein coupled receptor protein signaling pathway (Biological Process; BP) and located at the plasma membrane (Cellular Component; CC). Proteins with light green (M2) and dark green (M3) are mostly involved in regulation of apoptosis (BP) and located at the cell surface (CC). (b) Subnetwork of APP interactors involved in cell adhesion (BP) extracted from the extended APP/APLP2 protein-protein interaction network. (c) Subnetwork of APP interactors involved in vesicle-mediated transport (BP) extracted from the extended network. Red colored nodes represent the proteins from the YTH screen. Blue colored nodes indicate interactors extracted from the DBs. Node size represents relative degree of the nodes and the other interactions of nodes are neglected for the sake of simplicity. Dashed lines represent the interactions revealed by the YTH screening in human testis and solid lines are interactions from DBs. (d) Subnetwork of APP interactors involved in G-protein-coupled singnal pathways.

Mentions: First, we focused on local interactions of APP/APLP2, that is, the first direct interactors of APP/APLP2 and interactions between them. We identified 455 proteins connected to APP (Methods) including the partners identified by YTH (Figure 3a). All the proteins in the YTH data were newly found as interactors of APP except RANBP9, which was previously published as an APP interactor [9]. The absence of protein overlapping may be due to the fact that the YTH was performed using a library from human testis and the previous APP interactors were mainly identified in neuronal tissues. Indeed, published data indicate that 4% of the mammalian genome (more than 2,300 genes) encodes genes specifically expressed in the male germ line during or after the completion of spermatogenesis [39]. Regarding APLP2, we identified 6 proteins (including APP) as its interactors from the DBs which were highly specific to or strongly expressed in testis. In total, 1,803 interactions were identified between 457 proteins including APP and APLP2. Only one protein (BRCA1) among the nearest neighbors of APLP2 was not directly connected to APP which may reflect an isoform-specific role for APLP2.Figure 3


Amyloid precursor protein interaction network in human testis: sentinel proteins for male reproduction.

Silva JV, Yoon S, Domingues S, Guimarães S, Goltsev AV, da Cruz E Silva EF, Mendes JF, da Cruz E Silva OA, Fardilha M - BMC Bioinformatics (2015)

APP protein-protein interaction networks. (a) Local APP/APLP2 network. Proteins with light orange (M1) and dark orange (M4) are mostly involved in G-protein coupled receptor protein signaling pathway (Biological Process; BP) and located at the plasma membrane (Cellular Component; CC). Proteins with light green (M2) and dark green (M3) are mostly involved in regulation of apoptosis (BP) and located at the cell surface (CC). (b) Subnetwork of APP interactors involved in cell adhesion (BP) extracted from the extended APP/APLP2 protein-protein interaction network. (c) Subnetwork of APP interactors involved in vesicle-mediated transport (BP) extracted from the extended network. Red colored nodes represent the proteins from the YTH screen. Blue colored nodes indicate interactors extracted from the DBs. Node size represents relative degree of the nodes and the other interactions of nodes are neglected for the sake of simplicity. Dashed lines represent the interactions revealed by the YTH screening in human testis and solid lines are interactions from DBs. (d) Subnetwork of APP interactors involved in G-protein-coupled singnal pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384327&req=5

Fig3: APP protein-protein interaction networks. (a) Local APP/APLP2 network. Proteins with light orange (M1) and dark orange (M4) are mostly involved in G-protein coupled receptor protein signaling pathway (Biological Process; BP) and located at the plasma membrane (Cellular Component; CC). Proteins with light green (M2) and dark green (M3) are mostly involved in regulation of apoptosis (BP) and located at the cell surface (CC). (b) Subnetwork of APP interactors involved in cell adhesion (BP) extracted from the extended APP/APLP2 protein-protein interaction network. (c) Subnetwork of APP interactors involved in vesicle-mediated transport (BP) extracted from the extended network. Red colored nodes represent the proteins from the YTH screen. Blue colored nodes indicate interactors extracted from the DBs. Node size represents relative degree of the nodes and the other interactions of nodes are neglected for the sake of simplicity. Dashed lines represent the interactions revealed by the YTH screening in human testis and solid lines are interactions from DBs. (d) Subnetwork of APP interactors involved in G-protein-coupled singnal pathways.
Mentions: First, we focused on local interactions of APP/APLP2, that is, the first direct interactors of APP/APLP2 and interactions between them. We identified 455 proteins connected to APP (Methods) including the partners identified by YTH (Figure 3a). All the proteins in the YTH data were newly found as interactors of APP except RANBP9, which was previously published as an APP interactor [9]. The absence of protein overlapping may be due to the fact that the YTH was performed using a library from human testis and the previous APP interactors were mainly identified in neuronal tissues. Indeed, published data indicate that 4% of the mammalian genome (more than 2,300 genes) encodes genes specifically expressed in the male germ line during or after the completion of spermatogenesis [39]. Regarding APLP2, we identified 6 proteins (including APP) as its interactors from the DBs which were highly specific to or strongly expressed in testis. In total, 1,803 interactions were identified between 457 proteins including APP and APLP2. Only one protein (BRCA1) among the nearest neighbors of APLP2 was not directly connected to APP which may reflect an isoform-specific role for APLP2.Figure 3

Bottom Line: Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood.We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses.Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Signal Transduction, Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, 3810-193, Aveiro, Portugal. joanavieirasilva@ua.pt.

ABSTRACT

Background: Amyloid precursor protein (APP) is widely recognized for playing a central role in Alzheimer's disease pathogenesis. Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood. APP is involved in several biological functions which might be potentially important for male fertility, such as cell adhesion, cell motility, signaling, and apoptosis. Furthermore, APP superfamily members are known to be associated with fertility. Knowledge on the protein networks of APP in human testis and spermatozoa will shed light on the function of APP in the male reproductive system.

Results: We performed a Yeast Two-Hybrid screen and a database search to study the interaction network of APP in human testis and sperm. To gain insights into the role of APP superfamily members in fertility, the study was extended to APP-like protein 2 (APLP2). We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses. We classified significant features related to the human male reproduction for the APP interacting proteins and identified modules of proteins with similar functional roles which may show cooperative behavior for male fertility.

Conclusions: The present work provides the first report on the APP interactome in human testis. Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

Show MeSH
Related in: MedlinePlus