Divergent Functions of Rap1A and Rap1B in Endothelial Biology and Disease. Int J Mol Sci 2025 Jun 04;26(11)
Date
06/13/2025Pubmed ID
40508181Pubmed Central ID
PMC12155061DOI
10.3390/ijms26115372Scopus ID
2-s2.0-105007752487 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
Kosuru R, Chrzanowska MAuthor
Magdalena Chrzanowska PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsEndothelial Cells
Humans
Neoplasms
Neovascularization, Pathologic
Signal Transduction
rap GTP-Binding Proteins
rap1 GTP-Binding Proteins
