Transmembrane semaphorins are signaling molecules, controlling axonal wiring and embryo development, which are increasingly implicated in human diseases. Semaphorin 6C (Sema6C) is a poorly understood family member and its functional role is still unclear. Upon targeting Sema6C expression in a range of cancer cells, we observed dramatic growth suppression, decreased ERK phosphorylation, upregulation of cell cycle inhibitor proteins p21, p27 and p53, and the onset of cell senescence, associated with activation of autophagy. These data are consistent with a fundamental requirement for Sema6C to support viability and growth in cancer cells. Mechanistically, we unveiled a novel signaling pathway elicited by Sema6C, and dependent on its intracellular domain, mediated by tyrosine kinases c-Abl and Focal Adhesion Kinase (FAK). Sema6C was found in complex with c-Abl, and induced its phosphorylation, which in turn led to FAK activation, independent of cell–matrix adhesion. Sema6C-induced FAK activity was furthermore responsible for increased nuclear localization of YAP transcriptional regulator. Moreover, Sema6C conferred YAP signaling-dependent long-term cancer cell survival upon nutrient deprivation. In conclusion, our findings demonstrate that Sema6C elicits a cancer promoting-signaling pathway sustaining cell viability and self-renewal, independent of growth factors and nutrients availability.

SEMA6C: a novel adhesion-independent FAK and YAP activator, required for cancer cell viability and growth / Fard, D.; Testa, E.; Panzeri, V.; Rizzolio, S.; Bianchetti, G.; Napolitano, V.; Masciarelli, S.; Fazi, F.; Maulucci, G.; Scicchitano, B. M.; Sette, C.; Viscomi, M. T.; Tamagnone, L.. - In: CELLULAR AND MOLECULAR LIFE SCIENCES. - ISSN 1420-682X. - 80:4(2023), pp. 1-15. [10.1007/s00018-023-04756-1]

SEMA6C: a novel adhesion-independent FAK and YAP activator, required for cancer cell viability and growth

Masciarelli S.;Fazi F.;
2023

Abstract

Transmembrane semaphorins are signaling molecules, controlling axonal wiring and embryo development, which are increasingly implicated in human diseases. Semaphorin 6C (Sema6C) is a poorly understood family member and its functional role is still unclear. Upon targeting Sema6C expression in a range of cancer cells, we observed dramatic growth suppression, decreased ERK phosphorylation, upregulation of cell cycle inhibitor proteins p21, p27 and p53, and the onset of cell senescence, associated with activation of autophagy. These data are consistent with a fundamental requirement for Sema6C to support viability and growth in cancer cells. Mechanistically, we unveiled a novel signaling pathway elicited by Sema6C, and dependent on its intracellular domain, mediated by tyrosine kinases c-Abl and Focal Adhesion Kinase (FAK). Sema6C was found in complex with c-Abl, and induced its phosphorylation, which in turn led to FAK activation, independent of cell–matrix adhesion. Sema6C-induced FAK activity was furthermore responsible for increased nuclear localization of YAP transcriptional regulator. Moreover, Sema6C conferred YAP signaling-dependent long-term cancer cell survival upon nutrient deprivation. In conclusion, our findings demonstrate that Sema6C elicits a cancer promoting-signaling pathway sustaining cell viability and self-renewal, independent of growth factors and nutrients availability.
2023
FAK; kinase; semaphorin; signaling pathway; YAP
01 Pubblicazione su rivista::01a Articolo in rivista
SEMA6C: a novel adhesion-independent FAK and YAP activator, required for cancer cell viability and growth / Fard, D.; Testa, E.; Panzeri, V.; Rizzolio, S.; Bianchetti, G.; Napolitano, V.; Masciarelli, S.; Fazi, F.; Maulucci, G.; Scicchitano, B. M.; Sette, C.; Viscomi, M. T.; Tamagnone, L.. - In: CELLULAR AND MOLECULAR LIFE SCIENCES. - ISSN 1420-682X. - 80:4(2023), pp. 1-15. [10.1007/s00018-023-04756-1]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1678341
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