Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins.
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.
Ivankovic-Dikic
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Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S- 75124, Sweden. Ivan.Dikic@licr.uu.se
Grönroos
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Blaukat
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Barth
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BU
Dikic
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D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D003598:Cytoskeletal Proteins; D006133:Growth Substances; D007328:Insulin; D016023:Integrins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496063:Pxn protein, rat; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D020932:Nerve Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496052:Ptk2 protein, rat; C496054:Ptk2b protein, rat; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases