Rap1a, also known as Ras-associated protein 1A, is a member of the Ras subfamily of small GTP-binding proteins. It participates in multiple cellular processes such as cell adhesion, migration, and intracellular signaling pathways. It has been linked to pathways like ERK, Akt, and those related to mTORC1 activation, playing a significant role in maintaining normal physiological functions and in disease-related processes [1,2,4,6]. Genetic models, especially knockout (KO) mouse models, are valuable for studying Rap1a's function.

In orthodontic force-related studies, knockdown of CD97, which acts through the Rap1a/ERK pathway, partially rescued osteoclast differentiation, suggesting that Rap1a inhibition can increase osteoclast activity and accelerate tooth movement [1]. In hepatocytes, Rap1a activation suppresses gluconeogenic gene expression and glucose production, while its silencing has the opposite effect. Statins, which inhibit Rap1a's geranylgeranylation, stimulate hepatic gluconeogenesis and increase fasting blood glucose in obese mice [2]. In macrophages, knockdown of Rap1A inhibited pro-inflammatory cytokines induced by homocysteine [3].

In metabolic dysfunction-associated liver diseases, activation of hepatic Rap1A is suppressed in obese mice, and restoring its activity decreases liver steatosis by inhibiting mTORC1 activation [4]. In the lung endothelium, Rap1A knockdown increased store-operated calcium entry, leading to increased NFAT1 nuclear translocation, elevated pro-inflammatory cytokines, and endothelial hyperpermeability, while EC-specific Rap1A knockout mice showed an inflammatory lung phenotype [5]. In esophageal squamous cell carcinoma, Rap1A promoted metastasis by stimulating cell migration and invasion, possibly through the AKT signaling pathway [6].

In conclusion, Rap1a is involved in diverse biological functions, including osteoclast differentiation, hepatic glucose homeostasis, macrophage inflammation, liver steatosis, lung vascular integrity, and cancer metastasis. Studies using KO mouse models and other loss-of-function experiments have revealed its role in these processes, providing insights into diseases such as orthodontic-related bone remodeling, type 2 diabetes, atherosclerosis, metabolic liver diseases, lung inflammation, and cancer.