Abstract
Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin β1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin β1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin β1 and promotes neuroblastoma cell migration.
Keywords:
FAK; cell migration; Neogenin-1; Netrin-1; integrin-β1 activation; metastasis; neuroblastoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Adhesion
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Cell Movement
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Protein-Tyrosine Kinases
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Integrin beta1*
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Membrane Proteins
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Mice
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Netrin-1
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Neuroblastoma*
Substances
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Integrin beta1
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Membrane Proteins
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neogenin
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Netrin-1
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
Grants and funding
This work was supported by the Comisión Nacional de Investigación Científica y Tecnológica [21130521]; Fondo Nacional de Desarrollo Científico y Tecnológico [1140697]; Fondo Nacional de Desarrollo Científico y Tecnológico [1180495]; Red Temática de Investigación Cooperativa en Cancer [RD12/0036/0027]; SAF [SAF2015-65175-R]; Red Temática de Investigación Cooperativa en Cancer [RD12/0036/0027]; PSG: Ministerio de Ciencia, Innovación y Universidades and FEDER funds (RTI2018-093596); JGC: Ministerio de Economía y Competitividad of Spain (PI17CIII/00013), Consejería de Educación, Juventud y Deporte, Comunidad de Madrid (P2017/BMD-3692), Fundación Oncohematología Infantil, AFANION, and Asociación Pablo Ugarte.