Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
Cell Mol Life Sci. 2023 Mar 31;80(4):111. doi: 10.1007/s00018-023-04756-1.
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.
跨膜信号素是一类信号分子，在轴突布线和胚胎发育中起调控作用，越来越多的信号素与人类疾病有关。信号素 6C（Sema6C）是一个了解甚少的家族成员，其功能作用尚不清楚。在一系列癌细胞中靶向表达 Sema6C 后，我们观察到显著的生长抑制、ERK 磷酸化减少、细胞周期抑制剂蛋白 p21、p27 和 p53 的上调，以及细胞衰老的发生，同时伴随着自噬的激活。这些数据表明 Sema6C 对癌细胞的存活和生长至关重要。在机制上，我们揭示了 Sema6C 诱导的一种新的信号通路，该通路依赖于其细胞内结构域，由酪氨酸激酶 c-Abl 和黏着斑激酶（FAK）介导。Sema6C 与 c-Abl 形成复合物，并诱导其磷酸化，进而导致 FAK 激活，而不依赖于细胞基质黏附。Sema6C 诱导的 FAK 活性还导致 YAP 转录调节剂的核内定位增加。此外，Sema6C 在营养缺乏时赋予 YAP 信号依赖性的长期癌细胞存活能力。总之，我们的研究结果表明，Sema6C 引发了一种促进癌症的信号通路，维持细胞的存活和自我更新，而不依赖于生长因子和营养物质的可用性。
