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Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts.

Palacios-Moreno J, Foltz L, Guo A, Stokes MP, Kuehn ED, George L, Comb M, Grimes ML - PLoS Comput. Biol. (2015)

Bottom Line: Clusters of proteins in these networks are indicative of functional signaling pathways.The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN.Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Sciences, Center for Structural and Functional Neuroscience, University of Montana, Missoula, Montana, United States of America.

ABSTRACT
Protein phosphorylation plays a central role in creating a highly dynamic network of interacting proteins that reads and responds to signals from growth factors in the cellular microenvironment. Cells of the neural crest employ multiple signaling mechanisms to control migration and differentiation during development. It is known that defects in these mechanisms cause neuroblastoma, but how multiple signaling pathways interact to govern cell behavior is unknown. In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endosomes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half of the receptor tyrosine kinases in the human genome. Data were analyzed using a combination of graph theory and pattern recognition techniques that resolve data structure into networks that incorporate statistical relationships and protein-protein interaction data. Clusters of proteins in these networks are indicative of functional signaling pathways. The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN. Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT. The results suggest a mechanism to distinguish signaling responses to activation of different receptors, or combinations of receptors, that govern the behavior of the neural crest, which gives rise to neuroblastoma.

No MeSH data available.


Related in: MedlinePlus

Collaborative groups of RTKs.Interaction networks show proteins that co-cluster and have Spearman correlation > 0.5 (yellow edges) or are known to interact from PPI databases (grey edges) with ALK, PDGFRA, FGFR1, and IGFR1 (A); EGFR, DDR2, EPHA2, EPHB3, and PDGFRB (B). Only edges linked to RTKs are shown. Proteins are grouped by the number of interactions with RTKs (e.g. the group in the center containing PAG1 and BCAR1 in A interacts with all four RTKs). Nodes were filtered to exclude those with lowest representation in the phosphoproteomic data. Node size and color indicates total phosphorylation as in Fig 2. Proteins that are both known to interact and have a positive correlation have two edges (e.g. ALK edges connecting FYN, SHC1, and IRS1). PAG1, FYN, and PIK3R2, the only nodes in common to both networks, are highlighted in green.
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pcbi.1004130.g003: Collaborative groups of RTKs.Interaction networks show proteins that co-cluster and have Spearman correlation > 0.5 (yellow edges) or are known to interact from PPI databases (grey edges) with ALK, PDGFRA, FGFR1, and IGFR1 (A); EGFR, DDR2, EPHA2, EPHB3, and PDGFRB (B). Only edges linked to RTKs are shown. Proteins are grouped by the number of interactions with RTKs (e.g. the group in the center containing PAG1 and BCAR1 in A interacts with all four RTKs). Nodes were filtered to exclude those with lowest representation in the phosphoproteomic data. Node size and color indicates total phosphorylation as in Fig 2. Proteins that are both known to interact and have a positive correlation have two edges (e.g. ALK edges connecting FYN, SHC1, and IRS1). PAG1, FYN, and PIK3R2, the only nodes in common to both networks, are highlighted in green.

Mentions: Edges from the neuroblastoma network shown in S1 Fig were filtered to show only edges among proteins that co-clustered based on Spearman, Euclidean, or hybrid Spearman-Euclidean dissimilarity. Nodes are graphed as in Fig 1 using an edge-weighted, spring-embedded layout. Small isolated groups with limited interactions are at the bottom of the figure. Proteins that have no interaction edges within clusters are not shown. PNCPs in aggregated, co-clustering collaborative groups, indicated by shaded regions, are displayed in Fig 3. (The dark blue node next to the region shaded in green is CDK1 phosphorylated on its inhibitory site.)


Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts.

Palacios-Moreno J, Foltz L, Guo A, Stokes MP, Kuehn ED, George L, Comb M, Grimes ML - PLoS Comput. Biol. (2015)

Collaborative groups of RTKs.Interaction networks show proteins that co-cluster and have Spearman correlation > 0.5 (yellow edges) or are known to interact from PPI databases (grey edges) with ALK, PDGFRA, FGFR1, and IGFR1 (A); EGFR, DDR2, EPHA2, EPHB3, and PDGFRB (B). Only edges linked to RTKs are shown. Proteins are grouped by the number of interactions with RTKs (e.g. the group in the center containing PAG1 and BCAR1 in A interacts with all four RTKs). Nodes were filtered to exclude those with lowest representation in the phosphoproteomic data. Node size and color indicates total phosphorylation as in Fig 2. Proteins that are both known to interact and have a positive correlation have two edges (e.g. ALK edges connecting FYN, SHC1, and IRS1). PAG1, FYN, and PIK3R2, the only nodes in common to both networks, are highlighted in green.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401789&req=5

pcbi.1004130.g003: Collaborative groups of RTKs.Interaction networks show proteins that co-cluster and have Spearman correlation > 0.5 (yellow edges) or are known to interact from PPI databases (grey edges) with ALK, PDGFRA, FGFR1, and IGFR1 (A); EGFR, DDR2, EPHA2, EPHB3, and PDGFRB (B). Only edges linked to RTKs are shown. Proteins are grouped by the number of interactions with RTKs (e.g. the group in the center containing PAG1 and BCAR1 in A interacts with all four RTKs). Nodes were filtered to exclude those with lowest representation in the phosphoproteomic data. Node size and color indicates total phosphorylation as in Fig 2. Proteins that are both known to interact and have a positive correlation have two edges (e.g. ALK edges connecting FYN, SHC1, and IRS1). PAG1, FYN, and PIK3R2, the only nodes in common to both networks, are highlighted in green.
Mentions: Edges from the neuroblastoma network shown in S1 Fig were filtered to show only edges among proteins that co-clustered based on Spearman, Euclidean, or hybrid Spearman-Euclidean dissimilarity. Nodes are graphed as in Fig 1 using an edge-weighted, spring-embedded layout. Small isolated groups with limited interactions are at the bottom of the figure. Proteins that have no interaction edges within clusters are not shown. PNCPs in aggregated, co-clustering collaborative groups, indicated by shaded regions, are displayed in Fig 3. (The dark blue node next to the region shaded in green is CDK1 phosphorylated on its inhibitory site.)

Bottom Line: Clusters of proteins in these networks are indicative of functional signaling pathways.The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN.Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Sciences, Center for Structural and Functional Neuroscience, University of Montana, Missoula, Montana, United States of America.

ABSTRACT
Protein phosphorylation plays a central role in creating a highly dynamic network of interacting proteins that reads and responds to signals from growth factors in the cellular microenvironment. Cells of the neural crest employ multiple signaling mechanisms to control migration and differentiation during development. It is known that defects in these mechanisms cause neuroblastoma, but how multiple signaling pathways interact to govern cell behavior is unknown. In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endosomes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half of the receptor tyrosine kinases in the human genome. Data were analyzed using a combination of graph theory and pattern recognition techniques that resolve data structure into networks that incorporate statistical relationships and protein-protein interaction data. Clusters of proteins in these networks are indicative of functional signaling pathways. The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN. Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT. The results suggest a mechanism to distinguish signaling responses to activation of different receptors, or combinations of receptors, that govern the behavior of the neural crest, which gives rise to neuroblastoma.

No MeSH data available.


Related in: MedlinePlus