The KDEL receptor signalling cascade targets focal adhesion kinase on focal adhesions and invadopodia
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Carmen Ruggiero1, Mauro Grossi1, Giorgia Fragassi2, Antonella Di Campli3, Carmine Di Ilio4, Alberto Luini3 and Michele Sallese4,5
1CNRS, NEOGENEX CNRS International Associated Laboratory, Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, Sophia Antipolis, Valbonne, France
2Department of Medicine and Agency Sciences, 'G. d'Annunzio' University of Chieti–Pescara, Regional Health Care Agency of Abruzzo, Pescara, Italy
3Institute of Protein Biochemistry, National Research Council, Naples, Italy
4Department of Medical, Oral and Biotechnological Sciences, 'G. d'Annunzio' University of Chieti–Pescara, Chieti, Italy
5Centre for Research on Ageing and Translational Medicine (CeSI-MeT), 'G. d'Annunzio' University of Chieti–Pescara, Chieti, Italy
Michele Sallese, email: Michele.email@example.com
Keywords: membrane trafficking; cell signalling; KDEL receptor; Src; FAK
Received: November 11, 2016 Accepted: December 13, 2017 Published: December 19, 2017
Membrane trafficking via the Golgi-localised KDEL receptor activates signalling cascades that coordinate both trafficking and other cellular functions, including autophagy and extracellular matrix degradation. In this study, we provide evidence that membrane trafficking activates KDEL receptor and the Src family kinases at focal adhesions of HeLa cells, where this phosphorylates ADP-ribosylation factor GTPase-activating protein with SH3 domain, ankyrin repeat and PH domain (ASAP)1 and focal adhesion kinase (FAK). Previous studies have reported extracellular matrix degradation at focal adhesions. Here, matrix degradation was not seen at focal adhesions, although it occurred at invadopodia, where it was increased by KDEL receptor activation. This activation of KDEL receptor at invadopodia of A375 cells promoted recruitment and phosphorylation of FAK on tyrosines 397 and 861. From the functional standpoint, FAK overexpression inhibited steady-state and KDEL-receptor-stimulated extracellular matrix degradation, whereas overexpression of the FAK-Y397F mutant only inhibited KDEL-receptor-stimulated matrix degradation. Finally, we show that the Src and FAK activated downstream of KDEL receptor are part of parallel signalling pathways. In conclusion, membrane-traffic-generated signalling via KDEL receptor activates Src not only at the Golgi complex, but also at focal adhesions. By acting on Src and FAK, KDEL receptor increases invadopodia-mediated matrix degradation.
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