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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

The neuroblastoma cluster-filtered network (CFN).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.)
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pcbi.1004130.g002: The neuroblastoma cluster-filtered network (CFN).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.)

Mentions: We employed the inclusive clustering strategy to filter protein interaction edges to obtain the cluster-filtered network (CFN) shown in Fig 2. In this graph, only edges among proteins that co-clustered based on Spearman, Euclidean, or hybrid Spearman-Euclidean (SED) dissimilarity are shown. This CFN data structure is useful because graph layouts that treat edges like springs (edge-weighted, spring embedded; force-directed) aggregate proteins that share a statistical relationship and interact with one another, so nearest neighbors are likely to represent functional groups (regions highlighted in Fig 2).


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)

The neuroblastoma cluster-filtered network (CFN).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.)
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004130.g002: The neuroblastoma cluster-filtered network (CFN).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.)
Mentions: We employed the inclusive clustering strategy to filter protein interaction edges to obtain the cluster-filtered network (CFN) shown in Fig 2. In this graph, only edges among proteins that co-clustered based on Spearman, Euclidean, or hybrid Spearman-Euclidean (SED) dissimilarity are shown. This CFN data structure is useful because graph layouts that treat edges like springs (edge-weighted, spring embedded; force-directed) aggregate proteins that share a statistical relationship and interact with one another, so nearest neighbors are likely to represent functional groups (regions highlighted in Fig 2).

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