Kosuru Ramoji, Chrzanowska Magdalena
Versiti Blood Research Institute, P.O. Box 2178, Milwaukee, WI 53201-2178, USA.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Int J Mol Sci. 2025 Jun 4;26(11):5372. doi: 10.3390/ijms26115372.
Rap1A and Rap1B are closely related small GTPases that regulate endothelial adhesion, vascular integrity, and signaling pathways via effector domain interactions, with downstream effectors controlling integrins and cadherins. Although both isoforms are essential for vascular development, recent studies using endothelial-specific knockout models have uncovered distinct, non-redundant functions. Rap1B is a key regulator of VEGFR2 signaling, promoting angiogenesis, nitric oxide production, and immune evasion in tumors while restraining proinflammatory signaling in atherosclerosis. In contrast, Rap1A unexpectedly functions as a modulator of endothelial calcium homeostasis by restricting Orai1-mediated store-operated calcium entry, thereby limiting inflammatory responses and vascular permeability. New insights into Rap1 regulation highlight the roles of context-specific guanine nucleotide exchange factors, such as RasGRP3, and non-degradative ubiquitination in effector selection. Emerging data suggest that isoform-specific interactions between the Rap1 hypervariable regions and plasma membrane lipids govern their localization to distinct nanodomains, potentially influencing downstream signaling specificity. Together, these findings redefine the roles of Rap1A and Rap1B in endothelial biology and highlight their relevance in diseases such as tumor angiogenesis, atherosclerosis, and inflammatory lung injury. We discuss the therapeutic implications of targeting Rap1 isoforms in vascular pathologies and cancer, emphasizing the need for isoform-specific strategies that preserve endothelial homeostasis.
Rap1A和Rap1B是密切相关的小GTP酶，它们通过效应器结构域相互作用调节内皮细胞黏附、血管完整性和信号通路，其下游效应器控制整合素和钙黏蛋白。尽管这两种异构体对血管发育都至关重要，但最近使用内皮细胞特异性敲除模型的研究发现了它们独特的、非冗余的功能。Rap1B是VEGFR2信号传导的关键调节因子，在促进肿瘤血管生成、一氧化氮产生和免疫逃逸的同时，抑制动脉粥样硬化中的促炎信号传导。相比之下，Rap1A通过限制Orai1介导的储存性钙内流意外地发挥内皮细胞钙稳态调节剂的作用，从而限制炎症反应和血管通透性。对Rap1调节的新见解突出了特定背景下的鸟嘌呤核苷酸交换因子（如RasGRP3）和非降解性泛素化在效应器选择中的作用。新出现的数据表明，Rap1高变区与质膜脂质之间的异构体特异性相互作用决定了它们在不同纳米结构域中的定位，可能影响下游信号传导特异性。这些发现共同重新定义了Rap1A和Rap1B在内皮生物学中的作用，并突出了它们在肿瘤血管生成、动脉粥样硬化和炎症性肺损伤等疾病中的相关性。我们讨论了在血管病变和癌症中靶向Rap1异构体的治疗意义，强调了需要采用保留内皮细胞稳态的异构体特异性策略。
