Department of Life Sciences, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Int J Mol Sci. 2024 Oct 14;25(20):11043. doi: 10.3390/ijms252011043.
Growth-factor-induced cell signaling plays a crucial role in development; however, negative regulation of this signaling pathway is important for sustaining homeostasis and preventing diseases. SPROUTY2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase (RTK) signaling that binds to GRB2 during RTK activation and inhibits the GRB2-SOS complex, which inhibits RAS activation and attenuates the downstream RAS/ERK signaling cascade. SPRY was formerly discovered in but was later discovered in higher eukaryotes and was found to be connected to many developmental abnormalities. In several experimental scenarios, increased SPRY2 protein levels have been observed to be involved in both peripheral and central nervous system neuronal regeneration and degeneration. SPRY2 is a desirable pharmaceutical target for improving intracellular signaling activity, particularly in the RAS/ERK pathway, in targeted cells because of its increased expression under pathological conditions. However, the role of SPRY2 in brain-derived neurotrophic factor (BDNF) signaling, a major signaling pathway involved in nervous system development, has not been well studied yet. Recent research using a variety of small-animal models suggests that SPRY2 has substantial therapeutic promise for treating a range of neurological conditions. This is explained by its function as an intracellular ERK signaling pathway inhibitor, which is connected to a variety of neuronal activities. By modifying this route, SPRY2 may open the door to novel therapeutic approaches for these difficult-to-treat illnesses. This review integrates an in-depth analysis of the structure of SPRY2, the role of its major interactive partners in RTK signaling cascades, and their possible mechanisms of action. Furthermore, this review highlights the possible role of SPRY2 in neurodevelopmental disorders, as well as its future therapeutic implications.
生长因子诱导的细胞信号转导在发育中起着至关重要的作用；然而，这种信号通路的负调控对于维持内稳态和预防疾病也很重要。SPROUTY2（SPRY2）是一种有效的受体酪氨酸激酶（RTK）信号转导负调节剂，在 RTK 激活时与 GRB2 结合，并抑制 GRB2-SOS 复合物，从而抑制 RAS 激活并减弱下游 RAS/ERK 信号级联。SPRY 最初是在 中发现的，但后来在高等真核生物中也发现了它，并与许多发育异常有关。在几种实验情况下，观察到 SPRY2 蛋白水平的增加与外周和中枢神经系统神经元的再生和退化都有关。由于其在病理条件下的表达增加，SPRY2 是改善细胞内信号转导活性的理想药物靶点，特别是在 RAS/ERK 途径中，在靶细胞中。然而，SPRY2 在脑源性神经营养因子（BDNF）信号转导中的作用，BDNF 信号转导是神经系统发育的主要信号转导途径之一，尚未得到很好的研究。最近使用各种小动物模型的研究表明，SPRY2 在治疗一系列神经疾病方面具有很大的治疗潜力。这是因为它作为细胞内 ERK 信号通路抑制剂的功能，与多种神经元活动有关。通过修饰这条途径，SPRY2 可能为这些难以治疗的疾病开辟新的治疗方法。这篇综述综合分析了 SPRY2 的结构、其在 RTK 信号级联中主要相互作用伙伴的作用及其可能的作用机制。此外，本综述还强调了 SPRY2 在神经发育障碍中的可能作用及其未来的治疗意义。
