{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAP1B is a small GTPase that plays a central role in platelet activation and cardiovascular homeostasis. In platelets, RAP1B mediates inside‐out as well as outside‐in signaling by modulating the affinity of integrins—such as integrin αIIbβ3—for ligands like fibrinogen. Its activation is tightly regulated by agonists (for example, thrombin) through PI3K‐dependent pathways and by the coordinated input from multiple receptors (including PAR‐1, PAR‐4, and GPIb–IX–V), thereby ensuring proper thrombus formation and normal hemostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in platelets, RAP1B is indispensable for proper endothelial function and angiogenesis. In endothelial cells, RAP1B regulates β1‐integrin conformational activation, which is critical for adhesion, migration, and tube formation. Moreover, RAP1B participates in neuronal polarization by influencing axon specification via mTOR‐mediated signaling and Smurf2‐dependent degradation, and it also contributes to stem cell homeostasis by modulating telomere length and transcriptional regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, aberrant expression and regulation of RAP1B are linked to enhanced proliferation, migration, invasion, and metastasis in a variety of malignancies—including ovarian, hepatocellular, esophageal, colorectal, gastric, thyroid, glioblastoma, melanoma, lung adenocarcinoma, and acute myeloid leukemia. Multiple studies document that dysregulation of RAP1B, through mechanisms such as altered prenylation, changes in phosphorylation, and modulation by noncoding RNAs (for example, miR‐708, miR‐28‐5p, miR‐101‐3p, miR‐181, miR‐200b/c, as well as oncogenic long noncoding RNAs and circular RNAs), shifts cell–cell adhesion and cytoskeleton dynamics to drive aggressive tumor behavior and poor prognosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPost‐translational modifications are crucial in dictating the function of RAP1B. Phosphorylation by protein kinase A (PKA) induces conformational changes that affect its binding to regulators such as chaperones SmgGDS and CAP1, thereby modulating its prenylation and membrane localization. Reduced prenylation and altered subcellular distribution can diminish cell–cell adhesion and promote cell scattering, enhancing metastatic potential; similarly, viral proteins (e.g. HSV‐1 ICP4) manipulate RAP1B phosphorylation to reprogram cytoskeletal dynamics for efficient infection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional regulatory mechanisms of RAP1B include modulation by alternative splicing, deubiquitination, and specific genetic variations. For instance, differences in regulatory controls between RAP1B and its paralog RAP1A—such as phosphorylation‐dependent effects on prenylation via differential interaction with SmgGDS—and stabilizing actions by deubiquitinating enzymes (e.g. USP32) further refine its signaling output. Moreover, dysregulated RAP1B expression resulting from aberrant noncoding RNA networks (including competing endogenous RNA activity of long noncoding RNAs like AFAP1‐AS and LUADT1) has been linked to disease phenotypes ranging from aggressive cancers to metabolic and developmental abnormalities. Rare de novo mutations in RAP1B have also been implicated in congenital syndromic thrombocytopenia, while plexin‐mediated inactivation of RAP1 underscores its role in semaphorin signal transduction. Furthermore, recent ex vivo studies have identified microRNAs that regulate RAP1B in stored platelets."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "35"}, {"type": "fg_f", "ref": "32"}, {"type": "fg_fs", "start_ref": "36", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these studies position RAP1B as a multifaceted regulator whose finely tuned activity—via receptor-mediated signals, post‐translational modifications, and complex noncoding RNA networks—governs critical processes from platelet aggregation and vascular development to neuronal differentiation and tumor progression, as well as influencing susceptibility to viral infections and congenital disorders.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alessandra Bertoni, Seiji Tadokoro, Koji Eto, et al. 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