title: Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts.
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.
authors.affiliation: Division of Biological Sciences, Center for Structural and Functional Neuroscience, University of Montana, Missoula, Montana, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Palacios-Moreno
authors.affiliation: Division of Biological Sciences, Center for Structural and Functional Neuroscience, University of Montana, Missoula, Montana, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Foltz
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts, United States of America.
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts, United States of America.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Stokes
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Emily D
authors.initials: ED
authors.lastname: Kuehn
authors.affiliation: Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: George
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Comb
authors.affiliation: Division of Biological Sciences, Center for Structural and Functional Neuroscience, University of Montana, Missoula, Montana, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Grimes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106957:FYB1 protein, human; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases