Battistini Chiara, Tamagnone Luca
Department of Oncology, University of Torino c/o IRCCS, Str. Prov. 142, 10060, Candiolo (TO), Italy.
Candiolo Cancer Institute, IRCCS-FPO, Str. Prov. 142, 10060, Candiolo (TO), Italy.
Cell Mol Life Sci. 2016 Apr;73(8):1609-22. doi: 10.1007/s00018-016-2137-x. Epub 2016 Jan 21.
Semaphorins are signaling molecules playing pivotal roles not only as axon guidance cues, but are also involved in the regulation of a range of biological processes, such as immune response, angiogenesis and invasive tumor growth. The main functional receptors for semaphorins are plexins, which are large single-pass transmembrane molecules. Semaphorin signaling through plexins-the "classical" forward signaling-affects cytoskeletal remodeling and integrin-dependent adhesion, consequently influencing cell migration. Intriguingly, semaphorins and plexins can interact not only in trans, but also in cis, leading to differentiated and highly regulated signaling outputs. Moreover, transmembrane semaphorins can also mediate a so-called "reverse" signaling, by acting not as ligands but rather as receptors, and initiate a signaling cascade through their own cytoplasmic domains. Semaphorin reverse signaling has been clearly demonstrated in fruit fly Sema1a, which is required to control motor axon defasciculation and target recognition during neuromuscular development. Sema1a invertebrate semaphorin is most similar to vertebrate class-6 semaphorins, and examples of semaphorin reverse signaling in mammalians have been described for these family members. Reverse signaling is also reported for other vertebrate semaphorin subsets, e.g. class-4 semaphorins, which bear potential PDZ-domain interaction motifs in their cytoplasmic regions. Therefore, thanks to their various signaling abilities, transmembrane semaphorins can play multifaceted roles both in developmental processes and in physiological as well as pathological conditions in the adult.
信号素是一类信号分子，不仅在轴突导向中起关键作用，还参与一系列生物过程的调节，如免疫反应、血管生成和肿瘤侵袭性生长。信号素的主要功能受体是丛状蛋白，它们是大型单次跨膜分子。信号素通过丛状蛋白进行的信号传导——即“经典”正向信号传导——影响细胞骨架重塑和整合素依赖性黏附，进而影响细胞迁移。有趣的是，信号素和丛状蛋白不仅可以反式相互作用，还可以顺式相互作用，从而产生分化且高度调控的信号输出。此外，跨膜信号素还可以通过不作为配体而是作为受体发挥作用，介导所谓的“反向”信号传导，并通过其自身的细胞质结构域启动信号级联反应。信号素反向信号传导在果蝇Sema1a中已得到明确证实，它在神经肌肉发育过程中控制运动轴突解束和靶标识别。无脊椎动物信号素Sema1a与脊椎动物6类信号素最为相似，并且已经描述了这些家族成员在哺乳动物中的信号素反向信号传导实例。其他脊椎动物信号素亚类，如4类信号素，在其细胞质区域带有潜在的PDZ结构域相互作用基序，也有反向信号传导的报道。因此，由于其多样的信号传导能力，跨膜信号素在发育过程以及成体的生理和病理状况中都可以发挥多方面的作用。
