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A draft network of ligand-receptor-mediated multicellular signalling in human.

Ramilowski JA, Goldberg T, Harshbarger J, Kloppman E, Lizio M, Satagopam VP, Itoh M, Kawaji H, Carninci P, Rost B, Forrest AR - Nat Commun (2015)

Bottom Line: We also observe extensive autocrine signalling with approximately two-thirds of partners possibly interacting on the same cell type.We find that plasma membrane and secreted proteins have the highest cell-type specificity, they are evolutionarily younger than intracellular proteins, and that most receptors had evolved before their ligands.We provide an online tool to interactively query and visualize our networks and demonstrate how this tool can reveal novel cell-to-cell interactions with the prediction that mast cells signal to monoblastic lineages via the CSF1-CSF1R interacting pair.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045 Japan.

ABSTRACT
Cell-to-cell communication across multiple cell types and tissues strictly governs proper functioning of metazoans and extensively relies on interactions between secreted ligands and cell-surface receptors. Herein, we present the first large-scale map of cell-to-cell communication between 144 human primary cell types. We reveal that most cells express tens to hundreds of ligands and receptors to create a highly connected signalling network through multiple ligand-receptor paths. We also observe extensive autocrine signalling with approximately two-thirds of partners possibly interacting on the same cell type. We find that plasma membrane and secreted proteins have the highest cell-type specificity, they are evolutionarily younger than intracellular proteins, and that most receptors had evolved before their ligands. We provide an online tool to interactively query and visualize our networks and demonstrate how this tool can reveal novel cell-to-cell interactions with the prediction that mast cells signal to monoblastic lineages via the CSF1-CSF1R interacting pair.

No MeSH data available.


Related in: MedlinePlus

Relationship between protein subcellular localization, cell-type specificity and gene ages.(a) Breakdown of known subcellular localization of protein-coding genes expressed >1 TPM in at least one primary state for which protein ages were available. (b) Interquartile range distributions (whisker boxes) and relative cell-type specificity for each protein subcellular compartment from FANTOM5 primary cell expression profiles. Both secreted and plasma membrane proteins are significantly more cell-type specific than nuclear and cytoplasmic proteins (each Mann–Whitney U-test-adjusted P value<000.1). (c) Relative fractions of proteins at each evolutionary stage for selected subcellular localization (secreted, plasma membrane, nucleus, cytoplasmic and other) using the methods of Wagner21. All fractions at a given age add to 100%. (d) As in c but scaled for visualization purposes to the number of nuclear proteins. Both secreted (average age: 412.2 mya) and plasma membrane (average age: 517.2 mya) proteins are significantly younger than nuclear (average age: 663.1 mya) and cytoplasmic proteins (average age: 855.1 mya), each Mann–Whitney U-test-adjusted P value<000.1. Note: exact numbers of proteins for each subcellular localization class in each phylostrata are available in Supplementary Data 1.
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f1: Relationship between protein subcellular localization, cell-type specificity and gene ages.(a) Breakdown of known subcellular localization of protein-coding genes expressed >1 TPM in at least one primary state for which protein ages were available. (b) Interquartile range distributions (whisker boxes) and relative cell-type specificity for each protein subcellular compartment from FANTOM5 primary cell expression profiles. Both secreted and plasma membrane proteins are significantly more cell-type specific than nuclear and cytoplasmic proteins (each Mann–Whitney U-test-adjusted P value<000.1). (c) Relative fractions of proteins at each evolutionary stage for selected subcellular localization (secreted, plasma membrane, nucleus, cytoplasmic and other) using the methods of Wagner21. All fractions at a given age add to 100%. (d) As in c but scaled for visualization purposes to the number of nuclear proteins. Both secreted (average age: 412.2 mya) and plasma membrane (average age: 517.2 mya) proteins are significantly younger than nuclear (average age: 663.1 mya) and cytoplasmic proteins (average age: 855.1 mya), each Mann–Whitney U-test-adjusted P value<000.1. Note: exact numbers of proteins for each subcellular localization class in each phylostrata are available in Supplementary Data 1.

Mentions: Recently the FANTOM5 consortium used Cap Analysis of Gene Expression (CAGE) to generate a promoter level expression atlas12. Based on CAGE measurements across a collection of 975 human samples (primary cells, cell lines and tissues), gene expression profiles were classified as non-ubiquitous (cell-type restricted), ubiquitous-non-uniform and ubiquitous-uniform (housekeeping)12. Gene Ontology (GO)13 analysis of genes with cell-type-restricted expression showed their enrichment for proteins annotated with the terms receptor activity, plasma membrane (PM) and multicellular organismal process. This suggested that proteins involved in intercellular communication were more likely to have cell-type-restricted expression profiles. To explore this more systematically, we used protein experimental localization information1415 and computational predictions1617 (Methods) to classify human protein-coding genes (HGNC18 release 03 April 2014; http://www.genenames.org/cgi-bin/hgnc_downloads) based on the subcellular localization of the proteins they encode into: PM, secreted, cytosolic, nuclear, multiple and ‘other' proteins (Supplementary Data 1). Comparing the cell-type specificity of each class, we find that secreted and PM proteins are significantly more cell-type specific (Fig. 1) than proteins that localize to other cellular compartments (Mann–Whitney U-test, each adjusted P value<0.001). We also confirmed this trend using whole cell proteome data available for five haematopoietic primary cell types19 (Mann–Whitney U-test, each adjusted P value<0.001; Supplementary Fig. 1).


A draft network of ligand-receptor-mediated multicellular signalling in human.

Ramilowski JA, Goldberg T, Harshbarger J, Kloppman E, Lizio M, Satagopam VP, Itoh M, Kawaji H, Carninci P, Rost B, Forrest AR - Nat Commun (2015)

Relationship between protein subcellular localization, cell-type specificity and gene ages.(a) Breakdown of known subcellular localization of protein-coding genes expressed >1 TPM in at least one primary state for which protein ages were available. (b) Interquartile range distributions (whisker boxes) and relative cell-type specificity for each protein subcellular compartment from FANTOM5 primary cell expression profiles. Both secreted and plasma membrane proteins are significantly more cell-type specific than nuclear and cytoplasmic proteins (each Mann–Whitney U-test-adjusted P value<000.1). (c) Relative fractions of proteins at each evolutionary stage for selected subcellular localization (secreted, plasma membrane, nucleus, cytoplasmic and other) using the methods of Wagner21. All fractions at a given age add to 100%. (d) As in c but scaled for visualization purposes to the number of nuclear proteins. Both secreted (average age: 412.2 mya) and plasma membrane (average age: 517.2 mya) proteins are significantly younger than nuclear (average age: 663.1 mya) and cytoplasmic proteins (average age: 855.1 mya), each Mann–Whitney U-test-adjusted P value<000.1. Note: exact numbers of proteins for each subcellular localization class in each phylostrata are available in Supplementary Data 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525178&req=5

f1: Relationship between protein subcellular localization, cell-type specificity and gene ages.(a) Breakdown of known subcellular localization of protein-coding genes expressed >1 TPM in at least one primary state for which protein ages were available. (b) Interquartile range distributions (whisker boxes) and relative cell-type specificity for each protein subcellular compartment from FANTOM5 primary cell expression profiles. Both secreted and plasma membrane proteins are significantly more cell-type specific than nuclear and cytoplasmic proteins (each Mann–Whitney U-test-adjusted P value<000.1). (c) Relative fractions of proteins at each evolutionary stage for selected subcellular localization (secreted, plasma membrane, nucleus, cytoplasmic and other) using the methods of Wagner21. All fractions at a given age add to 100%. (d) As in c but scaled for visualization purposes to the number of nuclear proteins. Both secreted (average age: 412.2 mya) and plasma membrane (average age: 517.2 mya) proteins are significantly younger than nuclear (average age: 663.1 mya) and cytoplasmic proteins (average age: 855.1 mya), each Mann–Whitney U-test-adjusted P value<000.1. Note: exact numbers of proteins for each subcellular localization class in each phylostrata are available in Supplementary Data 1.
Mentions: Recently the FANTOM5 consortium used Cap Analysis of Gene Expression (CAGE) to generate a promoter level expression atlas12. Based on CAGE measurements across a collection of 975 human samples (primary cells, cell lines and tissues), gene expression profiles were classified as non-ubiquitous (cell-type restricted), ubiquitous-non-uniform and ubiquitous-uniform (housekeeping)12. Gene Ontology (GO)13 analysis of genes with cell-type-restricted expression showed their enrichment for proteins annotated with the terms receptor activity, plasma membrane (PM) and multicellular organismal process. This suggested that proteins involved in intercellular communication were more likely to have cell-type-restricted expression profiles. To explore this more systematically, we used protein experimental localization information1415 and computational predictions1617 (Methods) to classify human protein-coding genes (HGNC18 release 03 April 2014; http://www.genenames.org/cgi-bin/hgnc_downloads) based on the subcellular localization of the proteins they encode into: PM, secreted, cytosolic, nuclear, multiple and ‘other' proteins (Supplementary Data 1). Comparing the cell-type specificity of each class, we find that secreted and PM proteins are significantly more cell-type specific (Fig. 1) than proteins that localize to other cellular compartments (Mann–Whitney U-test, each adjusted P value<0.001). We also confirmed this trend using whole cell proteome data available for five haematopoietic primary cell types19 (Mann–Whitney U-test, each adjusted P value<0.001; Supplementary Fig. 1).

Bottom Line: We also observe extensive autocrine signalling with approximately two-thirds of partners possibly interacting on the same cell type.We find that plasma membrane and secreted proteins have the highest cell-type specificity, they are evolutionarily younger than intracellular proteins, and that most receptors had evolved before their ligands.We provide an online tool to interactively query and visualize our networks and demonstrate how this tool can reveal novel cell-to-cell interactions with the prediction that mast cells signal to monoblastic lineages via the CSF1-CSF1R interacting pair.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045 Japan.

ABSTRACT
Cell-to-cell communication across multiple cell types and tissues strictly governs proper functioning of metazoans and extensively relies on interactions between secreted ligands and cell-surface receptors. Herein, we present the first large-scale map of cell-to-cell communication between 144 human primary cell types. We reveal that most cells express tens to hundreds of ligands and receptors to create a highly connected signalling network through multiple ligand-receptor paths. We also observe extensive autocrine signalling with approximately two-thirds of partners possibly interacting on the same cell type. We find that plasma membrane and secreted proteins have the highest cell-type specificity, they are evolutionarily younger than intracellular proteins, and that most receptors had evolved before their ligands. We provide an online tool to interactively query and visualize our networks and demonstrate how this tool can reveal novel cell-to-cell interactions with the prediction that mast cells signal to monoblastic lineages via the CSF1-CSF1R interacting pair.

No MeSH data available.


Related in: MedlinePlus