Overview of RASA4 (CAPRI) and Its Function in Ras Signaling

RASA4, also known as RAS p21 protein activator 4 or CAPRI (Calcium-Promoted Ras Inactivator), is a member of the GAP1 family of GTPase-activating proteins that down-regulate Ras signaling in a calcium-dependent manner (www.ncbi.nlm.nih.gov). Like other Ras GAPs, RASA4 accelerates the intrinsic GTPase activity of Ras, converting Ras from its active GTP-bound form to an inactive GDP-bound form (www.ncbi.nlm.nih.gov). This terminates Ras-mediated signaling, notably the Ras–Raf–MEK–ERK (MAPK) pathway which controls gene expression, cell growth, and differentiation (www.ncbi.nlm.nih.gov). RASA4 is therefore a negative regulator of Ras signaling that links intracellular calcium signals to Ras inactivation (pharos.nih.gov). It is widely expressed across tissues (with especially high mRNA levels in immune organs like spleen and lymph nodes) (pmc.ncbi.nlm.nih.gov), suggesting a broad role in cellular signaling. Importantly, RASA4 was first characterized in 2001 as a calcium-regulated Ras GAP that localizes to the cytosol at rest and translocates to the plasma membrane upon Ca^2+ elevation (pmc.ncbi.nlm.nih.gov). Below, we discuss RASA4’s structure, biochemical activity, cellular localization, and involvement in key biological processes, citing recent research (including 2021–2024 studies) for the latest insights.

Domain Structure and Calcium-Regulated Activation

RASA4/CAPRI has a multi-domain architecture typical of the GAP1 subfamily of Ras GAPs (pmc.ncbi.nlm.nih.gov). It contains two tandem C2 domains at the N-terminus, a central GAP-related domain (GRD) that provides the catalytic Ras GTPase-activating function, and a C-terminal pleckstrin homology (PH) domain followed by a Bruton’s tyrosine kinase (Btk) motif (pmc.ncbi.nlm.nih.gov). The C2 domains are calcium-binding modules; notably, RASA4 (and the related RASAL1) contain the full complement of five acidic residues in each C2 domain required for Ca^2+ coordination (pmc.ncbi.nlm.nih.gov). Indeed, rises in intracellular Ca^2+ trigger RASA4’s C2 domains to bind lipid membranes, causing rapid translocation of RASA4 from the cytosol to the inner surface of the plasma membrane (pmc.ncbi.nlm.nih.gov). This Ca^2+-dependent membrane recruitment is essential for RASA4’s function – in unstimulated cells RASA4 is cytosolic, but upon a stimulus that raises Ca^2+ (such as receptor activation), RASA4 relocates to the plasma membrane where its GAP domain can access Ras proteins (pmc.ncbi.nlm.nih.gov). Interestingly, the PH domain of RASA4 appears atypical: unlike other GAP1 family members, RASA4’s PH domain does not bind phosphoinositides like PIP_2 or PIP_3 due to a Leu→Arg substitution at a key position (www.abcam.com). This suggests RASA4’s membrane targeting relies predominantly on Ca^2+/C2-domain interactions with anionic phospholipids (e.g. phosphatidylserine) rather than PH domain binding to phosphoinositide lipids. Consistent with this mechanism, deletion of the C-terminal PH-Btk module does not prevent Ca^2+-triggered translocation of RASA4 to the membrane (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), whereas mutations that disrupt Ca^2+ binding abolish membrane recruitment (pmc.ncbi.nlm.nih.gov). Thus, RASA4 acts as a calcium sensor in cells: it remains dormant in the cytosol until a rise in Ca^2+ induces it to attach to the membrane and become active as a Ras GTPase-accelerating protein (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

GTPase-Activating Function and Substrate Specificity

Primary biochemical function: RASA4’s GRD catalyzes the hydrolysis of GTP on Ras, turning off Ras signaling. In enzymatic terms, RASA4 provides an “arginine finger” into Ras’s active site, accelerating GTP hydrolysis by several orders of magnitude (as is typical for Ras GAPs) (pmc.ncbi.nlm.nih.gov). The primary substrates are the canonical Ras family small GTPases (H-Ras, N-Ras, K-Ras), which control the MAPK cascade. By stimulating Ras’s GTPase, RASA4 prevents prolonged activation of downstream ERK/MAPK signaling that would otherwise drive transcriptional programs for proliferation and differentiation (www.ncbi.nlm.nih.gov). Importantly, emerging research shows that RASA4 is a dual-specificity GAP under certain conditions. In addition to Ras, RASA4 can target the closely related GTPase Rap1 (a regulator of cell adhesion and other processes). In vitro and cell-based assays demonstrated that RASA4 (like several GAP1 family members) has measurable GAP activity toward Rap1, albeit weaker than its RasGAP activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This Rap1-GAP activity is calcium-regulated. A 2006 biochemical study (Kupzig et al., J. Biol. Chem., 2006) showed that RASA4’s ability to inactivate Rap1 is low at baseline but significantly enhanced when Ca^2+ triggers RASA4’s association with the plasma membrane (pmc.ncbi.nlm.nih.gov). Subsequent work (Dai et al., 2011) revealed the mechanism: Ca^2+ not only recruits RASA4 to the membrane, but also induces RASA4 homodimerization, and this oligomeric state favors Rap1 as a substrate (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Monomeric RASA4 predominantly acts as a RasGAP, whereas Ca^2+-induced RASA4 dimers exhibit increased Rap1GAP activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In live-cell experiments, a dimerization-deficient mutant of RASA4 had strong Ras-inactivating activity but was impaired in turning off Rap1, confirming that dimerization is crucial for RASA4’s RapGAP function (pmc.ncbi.nlm.nih.gov). These findings position RASA4 as a versatile GAP that can coordinate Ras and Rap1 signaling depending on cellular Ca^2+ levels. In effect, RASA4 acts as a calcium-sensitive switch: at moderate Ca^2+ it mainly inactivates Ras, and at high Ca^2+ it can simultaneously dampen Rap1 signaling, thereby tuning the balance between the Ras-ERK pathway and Rap1-mediated pathways (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This dual specificity, regulated by Ca^2+ and RASA4’s conformational state, is a distinctive feature that sets RASA4 apart from many other Ras GAPs (which typically do not act on Rap GTPases).

Subcellular Localization and Activation by Calcium

Under resting conditions, RASA4 is a cytosolic protein, but its active site must access membrane-bound Ras. RASA4 solves this by moving to the membrane only when needed: upon cell stimulation that raises intracellular Ca^2+, RASA4 rapidly translocates to the inner leaflet of the plasma membrane (pmc.ncbi.nlm.nih.gov). Early work by Lockyer and colleagues (2001) showed that agonists evoking Ca^2+ mobilization (e.g. histamine in certain cell types) cause GFP-tagged CAPRI to accumulate at the plasma membrane within seconds, coincident with Ras inactivation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This Ca^2+-triggered translocation is mediated by the two C2 domains which bind membrane phospholipids in the presence of Ca^2+ (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The localization switch is crucial: RASA4’s GAP activity is essentially confined to when and where it attaches to the membrane. Indeed, RASA4 has little to no Ras-GAP activity in solution; it becomes an effective Ras inhibitor only in the cellular context when recruited to Ras’s membrane compartment (pmc.ncbi.nlm.nih.gov). While at the membrane, RASA4 likely interacts with Ras at the inner plasma membrane (where Ras is anchored by lipid modifications) and possibly other signaling proteins. Notably, RASA4’s membrane residence can persist as long as Ca^2+ remains elevated – for example, CAPRI tends to stay membrane-bound during sustained calcium signals, unlike some related proteins that dissociate rapidly with Ca^2+ oscillations (pmc.ncbi.nlm.nih.gov). This behavior allows RASA4 to act as a brake on Ras for the duration of a calcium signal. Once Ca^2+ levels fall, RASA4 releases from the membrane and returns to the cytosolic inactive pool. In summary, subcellular localization is tightly coupled to RASA4 function: it is a cytosolic protein that dynamically relocalizes to carry out its GAP activity at the plasma membrane in response to second messenger (Ca^2+) signals (pmc.ncbi.nlm.nih.gov).

Role in Ras/MAPK Signaling and Calcium Signaling Pathways

By linking Ca^2+ signals to Ras inactivation, RASA4 serves as a key node in crosstalk between calcium signaling pathways and the Ras/MAPK pathway. Many cell stimuli – for instance, engagement of certain G-protein coupled receptors or immune cell receptors – trigger concurrent pathways: one leading to calcium release and another activating Ras. RASA4 is thought to sense the Ca^2+ increase and shut off Ras at the appropriate time, preventing overactivation of downstream ERK/MAPK signaling (www.ncbi.nlm.nih.gov). Lockyer et al. (2001) described CAPRI as an “amplitude sensor” for intracellular Ca^2+ bursts, meaning that RASA4 can translate the intensity of Ca^2+ signals into proportional Ras inactivation (pmc.ncbi.nlm.nih.gov). In practical terms, a mild stimulus causing a small Ca^2+ transient may only weakly recruit RASA4, allowing some Ras–ERK signaling to proceed; but a strong stimulus (with high Ca^2+) robustly brings RASA4 to the membrane (and in dimeric form), swiftly terminating Ras activity (and even dampening Rap1) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This provides a negative feedback loop in signaling: for example, in growth factor or immune receptor signaling, initial Ras activation can stimulate Ca^2+ release (via PLCγ generating IP_3), and the resulting Ca^2+ then recruits CAPRI/RASA4 to turn Ras off. Such feedback ensures transient Ras activation rather than sustained signaling. The outcome is finer control of the MAPK pathway, which is critical because prolonged Ras–ERK activity can lead to inappropriate gene transcription or cell proliferation. Consistent with this role, RASA4 loss can cause hyperactive Ras signaling. Cells lacking RASA4 show prolonged Ras–ERK pathway activation when calcium is elevated, since the usual Ca^2+-induced Ras shutoff is missing (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is evident in experimental models like CAPRI-knockdown neutrophils, which exhibit abnormally sustained Ras-GTP and downstream PI3K/Akt signaling upon stimulation (pmc.ncbi.nlm.nih.gov). Thus, in normal physiology RASA4 helps terminate Ras/MAPK signals in a timely, Ca^2+-dependent manner, preventing overactivation of pathways that drive proliferation or other responses.

Beyond the generic Ras/MAPK pathway, RASA4 also participates in specific signaling contexts. For example, RASA4 can function as an “adaptor” bridging Ras signaling to certain actin-regulating pathways. A 2005 Nature Immunology study showed that RASA4 (CAPRI) is required in Fcγ receptor-mediated phagocytosis in macrophages (pmc.ncbi.nlm.nih.gov). During phagocytosis of antibody-coated targets, calcium rises and CAPRI translocates to nascent phagocytic cups. There, RASA4 was found to interact with the Rho-family GTPases Cdc42 and Rac1 (key regulators of the actin cytoskeleton) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Although RASA4’s GAP domain is specific for Ras, it constitutively binds Cdc42/Rac1 and co-localizes with them at the membrane during phagocytosis (pmc.ncbi.nlm.nih.gov). In CAPRI knockout mice, macrophages showed impaired phagocytic engulfment and a reduced oxidative burst response, due to defective activation of Cdc42 and Rac1 at the phagocytic cup (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These findings suggest that RASA4 serves as a scaffold or adaptor, bringing together activated Ras (to turn it off) and the actin-remodeling GTPases (to help turn them on) in the precise spatial context of the forming phagosome (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In essence, RASA4 links the Fcγ receptor’s calcium signal to coordinated regulation of two GTPase modules: it terminates local Ras signals while facilitating Rac1/Cdc42-driven actin assembly needed for particle engulfment (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is a specialized example of how RASA4 integrates into signaling pathways beyond just Ras/MAPK, influencing cytoskeletal dynamics and innate immune responses.

Biological Functions in Immune Cells

RASA4 plays significant roles in the immune system, where stimuli often elevate Ca^2+ and require tight control of Ras and actin signaling. In innate immune cells such as neutrophils and macrophages, RASA4 has emerged as an important regulator:

• Chemotaxis and GPCR signaling in neutrophils: A recent study by Xu et al. (PNAS, 2021) identified RASA4/CAPRI as the crucial “Ras inhibitor” that enables neutrophils to properly adapt to chemoattractant gradients (pmc.ncbi.nlm.nih.gov). Neutrophils migrating toward signals (like fMLP or IL-8) experience a rapid Ras activation through GPCR pathways, which then must be attenuated (adaptation) to prevent saturation of the signaling cascade. Xu et al. showed that when CAPRI was knocked down in human neutrophil-like cells, the cells failed to turn off Ras signaling after initial stimulation – Ras-GTP remained abnormally high (non-adaptive) and downstream effectors like Akt, GSK-3β, and cofilin were hyper-phosphorylated (pmc.ncbi.nlm.nih.gov). This led to excessive F-actin polymerization and defective chemotaxis in steep chemoattractant gradients (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Essentially, without RASA4, neutrophils lost the ability to “reset” their signaling, becoming overstimulated and less directional in high signal conditions. Interestingly, the same cells showed supersensitive responses in shallow gradients – they would over-react to normally sub-threshold cues (pmc.ncbi.nlm.nih.gov). This paradoxical behavior underscores RASA4’s role in tuning signal sensitivity: with RASA4, neutrophils exhibit proper adaptation, allowing them to sense increases in chemoattractant over a wide concentration range (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The 2021 study concluded that CAPRI is an essential inhibitory component of the chemotactic signaling network, working in tandem with excitatory signals to optimize neutrophil navigation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is an expert confirmation that RASA4’s calcium-triggered Ras-GAP activity has a real-world function in immune cell migration.

• Fc receptor-mediated phagocytosis in macrophages: As mentioned, RASA4 was shown to be critical for efficient phagocytosis in a 2005 mouse study (Zhang et al., Nat. Immunol. 2005). CAPRI-deficient mice (Rasa4^–/–) were viable and developed normally, with no overt issues in basal immune cell populations (pmc.ncbi.nlm.nih.gov). However, when challenged, they had a severely impaired innate immune response to infections (pmc.ncbi.nlm.nih.gov). For instance, 80% of RASA4-knockout mice succumbed to Salmonella infection within 2 days, whereas 0% of wild-type mice died in that period (pmc.ncbi.nlm.nih.gov). They also showed dramatically reduced clearance of bacterial infections like Streptococcus pneumoniae in the lungs (pmc.ncbi.nlm.nih.gov). At the cellular level, macrophages from these knockout mice could bind antibody-coated bacteria but struggled to internalize them and mount a normal respiratory burst (pmc.ncbi.nlm.nih.gov). The underlying cause was traced to failure to properly activate Cdc42 and Rac1 during phagosome formation, due to loss of CAPRI’s adaptor function (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Thus, in real-world terms, RASA4 is required for host defense, linking calcium signals from engaged Fcγ receptors to the cytoskeletal rearrangements and microbicidal responses needed to engulf and destroy pathogens. These immune phenotypes highlight that, while RASA4’s enzymatic target is Ras, its absence has pleiotropic effects on immune cell function – but notably, those effects manifest in specific processes (phagocytosis, chemotaxis) where spatially and temporally controlled Ras inactivation is critical.

It is worth noting that RASA4 is one of several Ras regulators in immune cells. For example, in T-lymphocytes, Ras activation is triggered by the Ca^2+-dependent RasGEF RasGRP1, and it’s plausible that RASA4 provides a balancing negative feedback in that context as well. Although RASA4’s role in adaptive immunity is less well characterized, its ubiquitous expression and calcium-regulation suggest it may modulate signals downstream of the T-cell receptor or other lymphocyte receptors that induce calcium influx. The pronounced phenotypes in innate immunity, however, clearly establish RASA4 as a key signaling hub in immune responses, preventing overactivation of Ras pathways and coordinating them with cytoskeletal changes via Rac/Cdc42.

Roles in Cell Proliferation and Cancer

Given Ras’s central role in cell proliferation and oncogenic transformation, RASA4 has drawn interest for its potential influence on cancer-related pathways. By turning off Ras, RASA4 can act as a tumor suppressor-like factor, especially in tumors where Ras/MAPK signaling is driving growth. Recent cancer studies have started to examine RASA4 expression and function:

• A 2021 study by Chen et al. (published in Bioengineered, Dec 2021) investigated RASA4 in cervical squamous cell carcinoma (CESC). They found that RASA4 mRNA is significantly downregulated in cervical cancer tissues compared to normal tissue (pmc.ncbi.nlm.nih.gov). Low RASA4 levels correlated with poorer patient prognosis, suggesting RASA4 loss might contribute to tumor progression (pmc.ncbi.nlm.nih.gov). Experimentally, forcing RASA4 expression in cervical cancer cell lines (HeLa and C-33A) suppressed their proliferation, while CRISPR/Cas9 knockout of RASA4 enhanced proliferation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Mechanistically, the authors showed that RASA4 overexpression inactivates the HIF-1α signaling pathway in these cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Hypoxia-inducible factor 1α is often upregulated in tumors to promote angiogenesis and survival. In RASA4-overexpressing cells, HIF-1α transcriptional activity (measured by an HRE-luciferase reporter) was markedly reduced, and the levels of survivin (a pro-survival protein and HIF target) were diminished (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Conversely, RASA4 deletion led to heightened HIF-1α activity and survivin expression, effects which could be reversed by a HIF-1α inhibitor (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These results indicate that RASA4 suppresses tumor cell growth at least in part by down-regulating HIF-1α signaling, likely through its upstream effect on Ras. (Active Ras can stabilize HIF-1α via PI3K/AKT and MAPK pathways; thus RASA4 may impede those pro-HIF signals.) The study concluded that RASA4 is a promising inhibitor of cervical cancer cell proliferation and that its low expression in tumors could be an important diagnostic or prognostic marker (pmc.ncbi.nlm.nih.gov). Indeed, RASA4 expression had a high diagnostic value for distinguishing CESC tissue (ROC AUC ~0.986 in their analysis) (pmc.ncbi.nlm.nih.gov).

• Broader cancer genomic data also hint at RASA4’s role. While RASA4 is not among the most commonly mutated genes in cancer, loss-of-function mutations do occur. For instance, a 2022 study in Diffuse Large B-cell Lymphoma (DLBCL) identified a somatic missense mutation in RASA4 (D111N) in a relapsed tumor, predicted to be damaging (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Alongside mutations in other Ras regulators (like NF1 GTPase-activating protein and RASGRP4 GEF), the RASA4 mutation was associated with enhanced ERK/MAPK activation in the relapsed lymphoma cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This suggests that disrupting RASA4 can contribute to aberrant Ras pathway activation in cancer, potentially conferring growth advantage or treatment resistance. Indeed, RASA4’s closest homologs (like RASA1/p120 RasGAP and NF1) are well-known tumor suppressors, and although RASA4 is calcium-regulated and cell-context-specific, it appears to have a similar brake function on mitogenic signaling. Noonan syndrome and related “RASopathy” disorders (caused by germline Ras/MAPK pathway mutations) have not implicated RASA4 to date, but somatic alterations in RASA4 might collaborate with other oncogenic events to sustain Ras activity in certain contexts.

In summary, RASA4’s activity opposes oncogenic Ras signaling, and maintaining its function is ordinarily beneficial for keeping cell proliferation in check. When RASA4 is under-expressed or mutated, cells may experience more unchecked Ras/MAPK activity, which can contribute to tumorigenesis. While RASA4 is not as famous as major tumor suppressors like NF1, ongoing research (2021–2024) highlights its potential importance in cancer biology and even as a therapeutic target: for example, strategies to boost RASA4 activity or mimic its function could, in theory, help suppress Ras-driven tumor growth. Conversely, excessive RASA4 activity might dampen necessary Ras signals, so the cell must balance this carefully – which it achieves through the calcium-dependent regulatory mechanism described above.

Conclusion and Expert Perspectives

RASA4/CAPRI emerges as a multifaceted regulator that connects calcium second-messenger signals to the control of two critical small GTPases, Ras and Rap1. Its primary role is to serve as a calcium-triggered “off-switch” for Ras, ensuring that stimuli which elevate Ca^2+ (such as immune receptor engagement or growth factors) do not lead to runaway Ras/MAPK signaling (www.ncbi.nlm.nih.gov). This function is vital across various scenarios – from a neutrophil adjusting its sensitivity in a gradient (pmc.ncbi.nlm.nih.gov), to a macrophage coordinating actin remodeling for phagocytosis (pmc.ncbi.nlm.nih.gov), to a cell in a tumor suppressing proliferative signals (pmc.ncbi.nlm.nih.gov). Structurally, RASA4 is equipped with C2 domains to sense Ca^2+ and a GAP domain to execute GTP hydrolysis on Ras (and Rap1 when dimerized) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Experts in the field highlight RASA4 as an “inhibitory component” or brake in signaling pathways: for example, Xu et al. (2021) describe CAPRI as “essential for both the sensitivity and the GPCR-mediated adaptation of human neutrophils”, acting to locally control Ras activity and prevent overstimulation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Likewise, immunologists (Zhang et al. 2005) noted that “these results suggest that CAPRI provides a link between [FcγR signaling] and Cdc42/Rac1” (pmc.ncbi.nlm.nih.gov), underscoring its adaptor role beyond enzymatic activity. In the context of cancer, Chen et al. (2021) pointed out RASA4’s “tumor-suppressing role”, showing that restoring RASA4 can impair cancer cell proliferation by interfering with pro-growth pathways like HIF-1α (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). All these studies reinforce the concept that RASA4 is a critical regulatory node at the intersection of calcium signaling and Ras/Rap GTPase networks.

In conclusion, RASA4 (O43374) is a calcium-regulated Ras GAP that ensures appropriate termination of Ras signals and coordinates complex cellular responses. Its activity is finely tuned by intracellular Ca^2+ levels, subcellular localization, and oligomerization state, enabling it to function in processes ranging from chemotaxis and phagocytosis to growth control. Through recent advances (2021–2024), our understanding of RASA4 has expanded – revealing its dual Ras/Rap specificity, its role in immune cell signal adaptation, and its potential impact on cancer pathways. Ongoing research continues to uncover how this Calcium-Promoted Ras Inactivator contributes to normal physiology and how its dysregulation may lead to disease, solidifying RASA4’s place as an important molecular switch in human cellular signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

References:

1. Lockyer PJ et al. (2001). Curr. Biol. 11: 981–986. [PubMed ID: 11525734] – CAPRI regulates Ca^2+-dependent inactivation of the Ras-MAPK pathway (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
2. Zhang J et al. (2005). Nat. Immunol. 6(9): 911–919. [Published Sep 2005] – A critical role for CAPRI in FcγR-mediated phagocytosis (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
3. Kupzig S et al. (2006). J. Biol. Chem. 281(15): 9891–9900. [Published Apr 2006] – GAP1 family members are bifunctional Ras/Rap GAPs (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
4. Dai Y et al. (2011). J. Biol. Chem. 286(22): 19905–19916. [Published Jun 2011] – Ca^2+-dependent monomer-dimer switch in CAPRI controls Ras vs Rap GAP activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
5. Xu X et al. (2021). Proc. Natl. Acad. Sci. U.S.A. 118(43): e2002162118. [Published Oct 2021] – CAPRI enables neutrophils to chemotax through high-range gradients (Ras adaptation) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
6. Chen J et al. (2021). Bioengineered 12(2): 10723–10733. [Published Dec 2021] – RASA4 inhibits HIF-1α pathway to suppress cervical cancer cell proliferation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
7. Benoit A et al. (2022). Sci. Rep. 12: 779. [Published Jan 2022] – Mutations in Ras pathway regulators in relapsed DLBCL (includes RASA4 D111N) (pmc.ncbi.nlm.nih.gov).
8. Cherra SJ III & Lamb R (2024). Front. Mol. Neurosci. 17: 1352731. [Published Feb 2024] – Review: Intersections between Ras and Rap signaling (notes calcium-dependent RASA4 Ras/Rap GAP activity) (pmc.ncbi.nlm.nih.gov).

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14. AnnotationURLCitation(end_index=4832, start_index=4692, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=Ca%5E%7B2%2B%7D,dimeric%20forms%20of%20CAPRI%20exhibited')
15. AnnotationURLCitation(end_index=5078, start_index=4908, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=plasma%20membrane%20upon%20cell%20stimulation,monomers%20or%20homodimers%20through%20a')
16. AnnotationURLCitation(end_index=5427, start_index=5279, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=CAPRI%20is%20a%20member%20of,forms%20a%20hydrophobic%20face%20in')
17. AnnotationURLCitation(end_index=5597, start_index=5428, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=CAPRI%20increases%20upon%20cell%20stimulation,Ras%20and%20Rap1%20signaling%20pathways')
18. AnnotationURLCitation(end_index=6105, start_index=5940, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=domains%2C%20and%20although%20Rap1%20is,mechanisms%2C%20some%20GAPs%20have%20dual')
19. AnnotationURLCitation(end_index=6575, start_index=6420, title='RASA4 RAS p21 protein activator 4 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=10156#:~:text=that%20suppresses%20the%20Ras%2Fmitogen,Expression')
20. AnnotationURLCitation(end_index=7108, start_index=6978, title='GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1904491/#:~:text=GAP1,For%20this%20dual%20activity%2C%20regions')
21. AnnotationURLCitation(end_index=7244, start_index=7109, title='GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1904491/#:~:text=domain,association%20with%20the%20plasma%20membrane')
22. AnnotationURLCitation(end_index=7653, start_index=7518, title='GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1904491/#:~:text=domain,association%20with%20the%20plasma%20membrane')
23. AnnotationURLCitation(end_index=8025, start_index=7861, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=In%20addition%20to%20SynGAP%2C%20most,study%20suggests%20that%20modulation%20of')
24. AnnotationURLCitation(end_index=8167, start_index=8026, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=dimer%20formation,Ras%20and%20Rap1%20signaling%20pathways')
25. AnnotationURLCitation(end_index=8447, start_index=8287, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=%28Kupzig%20et%20al,translational%20modifications%20or%20second%20messenger')
26. AnnotationURLCitation(end_index=8589, start_index=8448, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=dimer%20formation,Ras%20and%20Rap1%20signaling%20pathways')
27. AnnotationURLCitation(end_index=8942, start_index=8801, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=dimer%20formation,Ras%20and%20Rap1%20signaling%20pathways')
28. AnnotationURLCitation(end_index=9479, start_index=9319, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=%28Kupzig%20et%20al,translational%20modifications%20or%20second%20messenger')
29. AnnotationURLCitation(end_index=9651, start_index=9480, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=RapGAP%20activity%20than%20RasGAP%20activity%2C,Ras%20and%20Rap1%20signaling%20pathways')
30. AnnotationURLCitation(end_index=10341, start_index=10208, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=as%20a%20Ras,a%20critical%20role%20in%20Fc%CE%B3R')
31. AnnotationURLCitation(end_index=10719, start_index=10583, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=intracellular%20Ca,We%20found%20that%20dimeric%20and')
32. AnnotationURLCitation(end_index=10889, start_index=10720, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=CAPRI%20increases%20upon%20cell%20stimulation,Ras%20and%20Rap1%20signaling%20pathways')
33. AnnotationURLCitation(end_index=11184, start_index=11019, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=dual%20RasGAP%20and%20RapGAP%20activities,and%20Rap1GAP%20activities%20of%20CAPRI')
34. AnnotationURLCitation(end_index=11340, start_index=11185, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=of%20the%20GAP1%20family%20that,RasGAP%20and%20RapGAP%20activities%20of')
35. AnnotationURLCitation(end_index=11780, start_index=11647, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=as%20a%20Ras,a%20critical%20role%20in%20Fc%CE%B3R')
36. AnnotationURLCitation(end_index=12354, start_index=12199, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=of%20the%20GAP1%20family%20that,RasGAP%20and%20RapGAP%20activities%20of')
37. AnnotationURLCitation(end_index=12915, start_index=12782, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=as%20a%20Ras,a%20critical%20role%20in%20Fc%CE%B3R')
38. AnnotationURLCitation(end_index=13657, start_index=13474, title='RASA4 RAS p21 protein activator 4 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=10156#:~:text=that%20suppresses%20the%20Ras%2Fmitogen,provided%20by%20RefSeq%2C%20Jul%202008')
39. AnnotationURLCitation(end_index=14007, start_index=13859, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=CAPRI%20is%20a%20member%20of,forms%20a%20hydrophobic%20face%20in')
40. AnnotationURLCitation(end_index=14472, start_index=14312, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=%28Kupzig%20et%20al,translational%20modifications%20or%20second%20messenger')
41. AnnotationURLCitation(end_index=14614, start_index=14473, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=dimer%20formation,Ras%20and%20Rap1%20signaling%20pathways')
42. AnnotationURLCitation(end_index=15522, start_index=15350, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20sense%20and%20migrate%20through,chemoattractants%2C%20as%20a%20result%20of')
43. AnnotationURLCitation(end_index=15695, start_index=15523, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=locally%20controls%20the%20GPCR,actin%20polymerization%3B%20and%20subsequent%20defective')
44. AnnotationURLCitation(end_index=16022, start_index=15866, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=gradients%20through%20adaptation,data%20reveal%20that%20CAPRI%20controls')
45. AnnotationURLCitation(end_index=16703, start_index=16549, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
46. AnnotationURLCitation(end_index=17097, start_index=16943, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
47. AnnotationURLCitation(end_index=17217, start_index=17098, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=Rac1,and%20Cdc42%20and%20Rac1%20and')
48. AnnotationURLCitation(end_index=17520, start_index=17366, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
49. AnnotationURLCitation(end_index=17860, start_index=17706, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
50. AnnotationURLCitation(end_index=17980, start_index=17861, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=Rac1,and%20Cdc42%20and%20Rac1%20and')
51. AnnotationURLCitation(end_index=18368, start_index=18214, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
52. AnnotationURLCitation(end_index=18504, start_index=18369, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=purified%20form,Fc%CE%B3R%20to%20Cdc42%20and%20Rac1')
53. AnnotationURLCitation(end_index=18882, start_index=18728, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
54. AnnotationURLCitation(end_index=19018, start_index=18883, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=purified%20form,Fc%CE%B3R%20to%20Cdc42%20and%20Rac1')
55. AnnotationURLCitation(end_index=19870, start_index=19698, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20sense%20and%20migrate%20through,chemoattractants%2C%20as%20a%20result%20of')
56. AnnotationURLCitation(end_index=20517, start_index=20361, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=gradients%20through%20adaptation,data%20reveal%20that%20CAPRI%20controls')
57. AnnotationURLCitation(end_index=20759, start_index=20628, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=calcium,data%20reveal%20that%20CAPRI%20controls')
58. AnnotationURLCitation(end_index=20932, start_index=20760, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=locally%20controls%20the%20GPCR,actin%20polymerization%3B%20and%20subsequent%20defective')
59. AnnotationURLCitation(end_index=21361, start_index=21231, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=GSK,findings%20show%20that%20CAPRI%20functions')
60. AnnotationURLCitation(end_index=21750, start_index=21583, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20provide%20first,mechanism%20largely%20remains%20elusive%2C%20although')
61. AnnotationURLCitation(end_index=21901, start_index=21751, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=recruit%20Ras%20inhibitor%2C%20CAPRI%2C%20to,mediated%20adaptation')
62. AnnotationURLCitation(end_index=22257, start_index=22090, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20provide%20first,mechanism%20largely%20remains%20elusive%2C%20although')
63. AnnotationURLCitation(end_index=22408, start_index=22258, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=recruit%20Ras%20inhibitor%2C%20CAPRI%2C%20to,mediated%20adaptation')
64. AnnotationURLCitation(end_index=23008, start_index=22855, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=Bacterial%20clearance%20in%20CAPRI,the%20expression%20of%20CAPRI%20in')
65. AnnotationURLCitation(end_index=23254, start_index=23106, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=macrophages%2C%20we%20examined%20the%20innate,5%7D%20CFU%2Fmouse')
66. AnnotationURLCitation(end_index=23549, start_index=23401, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=macrophages%2C%20we%20examined%20the%20innate,5%7D%20CFU%2Fmouse')
67. AnnotationURLCitation(end_index=23797, start_index=23668, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=whereas%20none%20of%20the%20controls,acquired')
68. AnnotationURLCitation(end_index=24120, start_index=23966, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
69. AnnotationURLCitation(end_index=24427, start_index=24273, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
70. AnnotationURLCitation(end_index=24563, start_index=24428, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=purified%20form,Fc%CE%B3R%20to%20Cdc42%20and%20Rac1')
71. AnnotationURLCitation(end_index=26657, start_index=26507, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=Luciferase%20reporter%20assays%20and%20LW6,Based%20on%20the%20TCGA')
72. AnnotationURLCitation(end_index=26937, start_index=26778, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=RAS%20p21%20protein%20activator%204,to%20determine%20the%20prognostic%20and')
73. AnnotationURLCitation(end_index=27266, start_index=27118, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=the%20CRISPR%2FCas9%20technology,was%20noted%20in%20the%20colony')
74. AnnotationURLCitation(end_index=27415, start_index=27267, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=the%20CRISPR%2FCas9%20technology,was%20noted%20in%20the%20colony')
75. AnnotationURLCitation(end_index=27714, start_index=27537, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=RASA4%20may%20negatively%20regulate%20HIF1%CE%B1,cells%20by%20inactivating%20the%20HIF1%CE%B1')
76. AnnotationURLCitation(end_index=27856, start_index=27715, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=Figure%205,Consistently%2C%20Western%20blotting%20results')
77. AnnotationURLCitation(end_index=28306, start_index=28168, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=that%20both%20RASA4%20and%20HIF1%CE%B1,As%20shown%20in')
78. AnnotationURLCitation(end_index=28473, start_index=28307, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=match%20at%20L366%20RASA4%20inactivated,revealed%20that%20survivin%20protein%20was')
79. AnnotationURLCitation(end_index=28759, start_index=28615, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=was%20also%20recorded%20in%20vivo,Our%20findings%20indicated')
80. AnnotationURLCitation(end_index=28913, start_index=28760, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=RASA4%20regulates%20proliferation%20through%20the,Furthermore%2C%20we')
81. AnnotationURLCitation(end_index=29539, start_index=29376, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=match%20at%20L44%20inactivating%20the,for%20targeted%20therapy%20against%20CESC')
82. AnnotationURLCitation(end_index=29811, start_index=29660, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=match%20at%20L251%20value%20of,of%20RASA4%20in%20CESC%20progression')
83. AnnotationURLCitation(end_index=30266, start_index=30152, title='Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8764096/#:~:text=SOS1%20%20,Possibly%20damaging')
84. AnnotationURLCitation(end_index=30368, start_index=30267, title='Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8764096/#:~:text=RASA2%20%20,N%2FA')
85. AnnotationURLCitation(end_index=30716, start_index=30567, title='Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8764096/#:~:text=hypothesized%20that%20RAS,In%20silico%20modeling%20indicated%20an')
86. AnnotationURLCitation(end_index=30842, start_index=30717, title='Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8764096/#:~:text=proteins,to%20a%20growth%20advantage%20in')
87. AnnotationURLCitation(end_index=32906, start_index=32723, title='RASA4 RAS p21 protein activator 4 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=10156#:~:text=that%20suppresses%20the%20Ras%2Fmitogen,provided%20by%20RefSeq%2C%20Jul%202008')
88. AnnotationURLCitation(end_index=33183, start_index=33016, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20provide%20first,mechanism%20largely%20remains%20elusive%2C%20although')
89. AnnotationURLCitation(end_index=33402, start_index=33248, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
90. AnnotationURLCitation(end_index=33618, start_index=33459, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=RAS%20p21%20protein%20activator%204,to%20determine%20the%20prognostic%20and')
91. AnnotationURLCitation(end_index=33928, start_index=33759, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=CAPRI%20increases%20upon%20cell%20stimulation,Ras%20and%20Rap1%20signaling%20pathways')
92. AnnotationURLCitation(end_index=34089, start_index=33929, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=%28Kupzig%20et%20al,translational%20modifications%20or%20second%20messenger')
93. AnnotationURLCitation(end_index=34569, start_index=34402, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20provide%20first,mechanism%20largely%20remains%20elusive%2C%20although')
94. AnnotationURLCitation(end_index=34720, start_index=34570, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=recruit%20Ras%20inhibitor%2C%20CAPRI%2C%20to,mediated%20adaptation')
95. AnnotationURLCitation(end_index=34989, start_index=34870, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=Rac1,and%20Cdc42%20and%20Rac1%20and')
96. AnnotationURLCitation(end_index=35415, start_index=35259, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=results%20indicate%20the%20tumor,Therefore%2C%20our%20results%20strongly')
97. AnnotationURLCitation(end_index=35593, start_index=35416, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=RASA4%20may%20negatively%20regulate%20HIF1%CE%B1,cells%20by%20inactivating%20the%20HIF1%CE%B1')
98. AnnotationURLCitation(end_index=36745, start_index=36574, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=RapGAP%20activity%20than%20RasGAP%20activity%2C,Ras%20and%20Rap1%20signaling%20pathways')
99. AnnotationURLCitation(end_index=36902, start_index=36746, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=gradients%20through%20adaptation,data%20reveal%20that%20CAPRI%20controls')
100. AnnotationURLCitation(end_index=37222, start_index=37081, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=CAPRI%20is%20a%20member%20of,cells%20but%20not%20in%20its')
101. AnnotationURLCitation(end_index=37356, start_index=37223, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=as%20a%20Ras,a%20critical%20role%20in%20Fc%CE%B3R')
102. AnnotationURLCitation(end_index=37660, start_index=37506, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=that%20the%20Ca%5E%7B2%2B%7D,defective%20activation%20of%20Cdc42%20and')
103. AnnotationURLCitation(end_index=37796, start_index=37661, title='A critical role for the Calcium-promoted Ras Inactivator in Fcγ receptor-mediated phagocytosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1464573/#:~:text=purified%20form,Fc%CE%B3R%20to%20Cdc42%20and%20Rac1')
104. AnnotationURLCitation(end_index=38077, start_index=37947, title='GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1904491/#:~:text=GAP1,For%20this%20dual%20activity%2C%20regions')
105. AnnotationURLCitation(end_index=38213, start_index=38078, title='GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1904491/#:~:text=domain,association%20with%20the%20plasma%20membrane')
106. AnnotationURLCitation(end_index=38561, start_index=38392, title='Ca2+-dependent Monomer and Dimer Formation Switches CAPRI Protein between Ras GTPase-activating Protein (GAP) and RapGAP Activities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3103366/#:~:text=CAPRI%20increases%20upon%20cell%20stimulation,Ras%20and%20Rap1%20signaling%20pathways')
107. AnnotationURLCitation(end_index=38722, start_index=38562, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=%28Kupzig%20et%20al,translational%20modifications%20or%20second%20messenger')
108. AnnotationURLCitation(end_index=39092, start_index=38920, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=Neutrophils%20sense%20and%20migrate%20through,chemoattractants%2C%20as%20a%20result%20of')
109. AnnotationURLCitation(end_index=39243, start_index=39093, title='Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8639426/#:~:text=recruit%20Ras%20inhibitor%2C%20CAPRI%2C%20to,mediated%20adaptation')
110. AnnotationURLCitation(end_index=39595, start_index=39418, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=RASA4%20may%20negatively%20regulate%20HIF1%CE%B1,cells%20by%20inactivating%20the%20HIF1%CE%B1')
111. AnnotationURLCitation(end_index=39737, start_index=39596, title='RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8809920/#:~:text=Figure%205,Consistently%2C%20Western%20blotting%20results')
112. AnnotationURLCitation(end_index=40013, start_index=39899, title='Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8764096/#:~:text=SOS1%20%20,Possibly%20damaging')
113. AnnotationURLCitation(end_index=40388, start_index=40224, title='Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10920261/#:~:text=In%20addition%20to%20SynGAP%2C%20most,study%20suggests%20that%20modulation%20of')