Abstract
Integration of signalling pathways initiated by receptor tyrosine kinases and integrins is essential for growth-factor-mediated biological responses. Here we show that co-stimulation of growth-factor receptors and integrins activates the focal-adhesion kinase (FAK) family to promote outgrowth of neurites in PC12 and SH-SY5Y cells. Pyk2 and FAK associate with adhesion-based complexes that contain epidermal growth factor (EGF) receptors, through their carboxy- and amino-terminal domains. Expression of the C-terminal domain of Pyk2 or of FAK is sufficient to block neurite outgrowth, but not activation of extracellular-signal-regulated kinase (ERK). Moreover, activation and autophosphorylation of Pyk2/FAK, as well as of effectors of their adhesion-targeting domains, such as paxillin, are important for propagation of signals that control neurite formation. Thus, Pyk2/FAK have important functions in signal integration proximal to integrin/growth-factor receptor complexes in neurons.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cytoskeletal Proteins / metabolism
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Enzyme Activation
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Epidermal Growth Factor / metabolism
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / metabolism
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Focal Adhesion Kinase 1
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Focal Adhesion Kinase 2
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Focal Adhesion Protein-Tyrosine Kinases
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Growth Substances / metabolism*
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Growth Substances / pharmacology
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Humans
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Insulin / metabolism
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Insulin / pharmacology
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Insulin-Like Growth Factor I / metabolism
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Insulin-Like Growth Factor I / pharmacology
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Integrins / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Nerve Growth Factor / metabolism
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Nerve Growth Factor / pharmacology
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Neurites / physiology*
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PC12 Cells
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Paxillin
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Phosphoproteins / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism*
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Rats
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Signal Transduction / physiology*
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Tumor Cells, Cultured
Substances
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Cytoskeletal Proteins
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Growth Substances
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Insulin
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Integrins
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PXN protein, human
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Paxillin
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Phosphoproteins
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Pxn protein, rat
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Epidermal Growth Factor
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Insulin-Like Growth Factor I
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Nerve Growth Factor
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ErbB Receptors
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Kinase 2
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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Ptk2 protein, rat
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Ptk2b protein, rat
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases