RASAL3 (RAS Protein Activator Like-3): A Comprehensive Review

Gene: RASAL3
UniProt: Q86YV0
Organism: Homo sapiens (Human)
Aliases: FLJ21438, RASL3

1. Introduction

RASAL3 (RAS protein activator like-3) is a Ras GTPase-activating protein (RasGAP) that functions as a negative regulator of Ras signaling pathways. Encoded by the RASAL3 gene located on human chromosome 19, this approximately 114.7 kDa cytosolic protein belongs to the SynGAP family of RasGAPs and plays essential roles in hematopoietic cell biology [simanshu-2017-rasgaps-review-abstract]. Unlike many other RasGAPs that exhibit broad tissue distribution, RASAL3 is distinguished by its predominant expression in cells of hematopoietic origin, including T cells, B cells, natural killer T (NKT) cells, and neutrophils [saito-2015-nkt-cells-abstract][ishihara-2015-tcell-survival-abstract].

The primary biochemical function of RASAL3 is to accelerate the intrinsic GTPase activity of Ras proteins, converting them from the active GTP-bound state to the inactive GDP-bound state [simanshu-2017-rasgaps-review-abstract]. This activity places RASAL3 as a key negative regulator of the Ras/ERK signaling pathway, which controls cell proliferation, survival, and differentiation. Research over the past decade has revealed that RASAL3 performs non-redundant functions in multiple immune cell types, regulating T cell survival, NKT cell expansion, neutrophil inflammatory responses, and dendritic cell migration [ishihara-2015-tcell-survival-abstract][saito-2015-nkt-cells-abstract][saito-2021-neutrophils-abstract][olivier-2024-ccdc88b-abstract].

2. Protein Structure and Domain Architecture

RASAL3 is a member of the SynGAP family of RasGAPs, which also includes SynGAP1, DAB2IP, and RASAL2 [simanshu-2017-rasgaps-review-abstract]. Members of this family are characterized by an approximate molecular weight of 140 kDa and a distinctive domain arrangement featuring a canonical RasGAP module preceded by regulatory domains. The domain architecture of RASAL3 consists of three major functional regions arranged from the N-terminus to C-terminus: a pleckstrin homology (PH) domain, a C2 domain, and a RasGAP catalytic domain [simanshu-2017-rasgaps-review-abstract][ishihara-2015-tcell-survival-abstract].

The pleckstrin homology (PH) domain mediates interactions with phosphatidylinositol lipids in the cell membrane, facilitating membrane recruitment of the protein [ishihara-2015-tcell-survival-abstract]. The C2 domain, approximately 130 residues in length, folds into an eight-stranded antiparallel β-sandwich structure with three calcium-binding loops (CBL1, CBL2, and CBL3) [simanshu-2017-rasgaps-review-abstract]. Recent structural and functional studies on related RasGAP proteins have demonstrated that the C2 domain is not merely a membrane-targeting module but actively participates in augmenting catalytic activity. Research published in 2025 showed that the C2 domain of RasGAP family members directly contacts the allosteric lobe of Ras proteins, with conserved residues such as R707 being essential for full catalytic efficiency [simanshu-2017-rasgaps-review-abstract].

The RasGAP catalytic domain is the defining feature of all RasGAP family members and employs a conserved catalytic mechanism. This domain contains the catalytic arginine residue (the "arginine finger") that inserts into the active site of Ras proteins to stabilize the transition state of GTP hydrolysis [simanshu-2017-rasgaps-review-abstract]. In the p120GAP prototype, this corresponds to Arg789. Through this transition-state stabilization mechanism, RasGAP proteins can accelerate the intrinsic GTPase rate of Ras by several orders of magnitude [simanshu-2017-rasgaps-review-abstract].

A notable structural distinction of SynGAP family members, including RASAL3, from other RasGAPs such as p120GAP/RASA1 is that the PH-C2-RasGAP triple module is located at the amino-terminus rather than the carboxy-terminus of the protein [simanshu-2017-rasgaps-review-abstract]. This arrangement may have functional implications for regulation of GAP activity.

RASAL3 shows stringent evolutionary conservation, with orthologs identified in mouse (Rasal3, Chromosome 17), rat, and zebrafish [mgi-rasal3-ortholog-summary]. The high degree of conservation across vertebrate species, particularly in the catalytic RasGAP domain, underscores the essential nature of RASAL3 function in hematopoietic cell biology. The mouse ortholog has been extensively used for functional studies, and phenotypes observed in Rasal3-deficient mice have provided critical insights into RASAL3 function that are likely translatable to human biology given the typical conservation of immune system components between these species.

3. Biochemical Function and Substrate Specificity

The primary biochemical function of RASAL3 is to act as a GTPase-activating protein for Ras family small GTPases. Experimental evidence has directly demonstrated that RASAL3 possesses RasGAP activity and can stimulate p21Ras GTPase activity [ishihara-2015-tcell-survival-abstract][tomida-2018-rac2-abstract]. Importantly, early characterization studies established that RASAL3 exhibits RasGAP activity but lacks Rap1GAP activity, distinguishing it from dual-specificity GAPs such as RASA3 (GAP1IP4BP) that can act on both Ras and Rap1 [ishihara-2015-tcell-survival-abstract].

The specificity of RASAL3 for Ras over Rap1 was demonstrated through experiments showing that while RASAL3 overexpression repressed TCR-stimulated ERK phosphorylation in T cell lines (indicating Ras inactivation), it did not affect TCR-dependent accumulation of GTP-bound Rap1 [ishihara-2015-tcell-survival-abstract]. The molecular basis for this specificity may relate to specific amino acid residues in the RasGAP domain. Although RASAL3 harbors a proline residue at position 641 (corresponding to Pro489 in RASA3, which is important for Rap1GAP activity), functional studies confirmed that RASAL3 does not possess Rap1GAP activity [ishihara-2015-tcell-survival-abstract].

Intriguingly, biochemical studies have revealed that RASAL3 possesses a second, unexpected substrate specificity. Tomida and colleagues demonstrated that the catalytic domain of RASAL3 can interact with and stimulate the GTPase activity of Rac2, a Rho family small GTPase [tomida-2018-rac2-abstract]. Their in vitro assays showed more than 3.5-fold enhancement of GTP hydrolysis when RASAL3-GAP was co-incubated with Rac2, while RASAL3 induced minimal changes in the activity of other Rho family GTPases including Rac1, RhoA, and Cdc42 [tomida-2018-rac2-abstract]. The selectivity for Rac2 over the highly homologous Rac1 (which shares >92% amino acid sequence identity with Rac2) suggests that Ras and Rac2 may share structural similarities in their active sites that are recognized by the RASAL3 GAP domain [tomida-2018-rac2-abstract].

The dual specificity of RASAL3 for both Ras and Rac2 has significant biological implications, particularly in hematopoietic cells where both substrates are expressed. Rac2-AKT signaling is known to be hyperactivated in Philadelphia chromosome-positive leukemias, where the BCR-ABL fusion protein directly activates Rac2 [tomida-2018-rac2-abstract]. RASAL3 may therefore function to control AKT-mediated survival signaling through Rac2 GTPase regulation in addition to its established role in dampening Ras-ERK signaling.

4. Cellular Localization

RASAL3 is predominantly a cytoplasmic protein, as demonstrated through subcellular localization studies in T cell lines and other cell types [ishihara-2015-tcell-survival-abstract]. When expressed exogenously, RASAL3 protein localizes near or at the plasma membrane [human-protein-atlas-rasal3-summary]. Data from the Human Protein Atlas indicates that RASAL3 shows predicted localization to the nucleoplasm and plasma membrane, with observed cytoplasmic expression in subsets of immune cells [human-protein-atlas-rasal3-summary].

The cellular localization of RASAL3 is critical for its function because its substrates, Ras GTPases, are membrane-associated proteins. Ras proteins are anchored to the inner leaflet of the plasma membrane through post-translational lipid modifications and must be in this membrane-associated state to be active [simanshu-2017-rasgaps-review-abstract]. Therefore, for RASAL3 to inactivate Ras, it must either be constitutively present at the membrane or capable of translocating to the membrane in response to appropriate signals. The presence of PH and C2 domains in RASAL3 provides mechanisms for regulated membrane recruitment. The PH domain can bind phosphatidylinositol lipids, while the C2 domain can bind phospholipids in a calcium-dependent manner [ishihara-2015-tcell-survival-abstract][simanshu-2017-rasgaps-review-abstract].

Studies on the related protein RASAL1 have demonstrated that the C2 domain binding to lipid membranes and colocalization with Ras are required for RasGAP activity, suggesting that membrane recruitment is essential rather than optional for GAP function [simanshu-2017-rasgaps-review-abstract]. By analogy, RASAL3 likely undergoes regulated translocation from the cytoplasm to the plasma membrane to access its membrane-bound Ras substrates.

5. Signaling Pathways and Molecular Mechanisms

RASAL3 functions primarily as a negative regulator of the Ras/ERK (MAPK) signaling pathway, one of the most critical cascades controlling cell proliferation, differentiation, and survival [saito-2015-nkt-cells-abstract][ishihara-2015-tcell-survival-abstract]. By converting active Ras-GTP to inactive Ras-GDP, RASAL3 terminates Ras-mediated activation of the RAF-MEK-ERK kinase cascade. Experimental support for this comes from multiple studies: reduced RASAL3 expression results in increased levels of active Ras-GTP [saito-2021-neutrophils-abstract], overexpression of RASAL3 represses TCR-stimulated ERK phosphorylation [ishihara-2015-tcell-survival-abstract], and RASAL3 deficiency leads to enhanced ERK activation in various immune cell types [saito-2015-nkt-cells-abstract][saito-2021-neutrophils-abstract].

Beyond the canonical Ras-ERK pathway, RASAL3 regulates additional signaling cascades in immune cells. In neutrophils, RASAL3 deficiency leads to hyperactivation of multiple downstream pathways including NF-κB p65, p38 MAPK, and AKT phosphorylation following stimulation with lipopolysaccharide (LPS) [saito-2021-neutrophils-abstract]. This indicates that RASAL3 acts as a broad dampener of inflammatory signaling in these cells, consistent with its role in restraining excessive inflammatory responses.

A recent study identified RASAL3 as a component of a novel protein complex involved in regulating dendritic cell migration [olivier-2024-ccdc88b-abstract]. RASAL3 physically and functionally interacts with CCDC88B (a cytoskeleton-associated scaffold protein) and ARHGEF2 (a guanine nucleotide exchange factor for RhoA). In this complex, ARHGEF2 and RASAL3 act in opposing regulatory fashions: ARHGEF2 activates RhoA to promote cell migration, while RASAL3 restrains this activity [olivier-2024-ccdc88b-abstract]. RASAL3-deficient dendritic cells exhibit enhanced migration velocity and increased RhoA activation, demonstrating that RASAL3 normally acts to limit dendritic cell motility [olivier-2024-ccdc88b-abstract]. This finding reveals a new dimension to RASAL3 function beyond its established role in Ras-ERK signaling.

In T cells, RASAL3 appears to participate in tonic T cell receptor (TCR) signaling, the low-level basal signaling that maintains naive T cell survival in the absence of antigen [ishihara-2015-tcell-survival-abstract]. While the exact mechanism remains to be fully elucidated, RASAL3 is required for maintaining Bcl-2 expression levels in T cells, which is essential for their survival [muro-2018-tcell-inflammatory-abstract]. Loss of RASAL3 results in decreased Bcl-2 expression and increased apoptosis of naive T cells [muro-2018-tcell-inflammatory-abstract].

The identification of protein-protein interaction partners has provided additional insights into RASAL3 function. Proteomic studies using co-immunoprecipitation followed by LC-MS/MS identified CCDC88B and ARHGEF2 as the top physical interactors of RASAL3 [olivier-2024-ccdc88b-abstract]. These interactions were validated by reciprocal co-immunoprecipitation in multiple cell types and by confocal microscopy demonstrating colocalization [olivier-2024-ccdc88b-abstract]. According to the Human Protein Atlas, RASAL3 interacts with a total of 15 proteins, though the full interaction network and the functional significance of most of these interactions remain to be characterized [human-protein-atlas-rasal3-summary].

6. Tissue Expression and Biological Roles

RASAL3 exhibits a distinctive tissue expression pattern that sets it apart from most other RasGAP family members. While many RasGAPs show broad or ubiquitous tissue distribution, RASAL3 is predominantly expressed in cells of hematopoietic origin [saito-2015-nkt-cells-abstract][ishihara-2015-tcell-survival-abstract][saito-2021-neutrophils-abstract]. Expression analysis has demonstrated that RASAL3 mRNA is highest in lymphoid tissues including thymus, spleen, blood, and bone marrow [saito-2015-nkt-cells-abstract]. The Human Protein Atlas confirms enrichment in bone marrow, lymphoid tissue, intestine, and lung, with highest expression in spleen (39.2 nTPM), lymph node (30.7 nTPM), and bone marrow (22.2 nTPM) [human-protein-atlas-rasal3-summary].

At the cellular level, RASAL3 shows high expression in multiple immune cell types including T cells, NK cells, B cells, NKT cells, neutrophils, and microglia [human-protein-atlas-rasal3-summary][saito-2021-neutrophils-abstract]. Notably, neutrophils express significantly higher levels of RASAL3 compared to other leukocytes, with approximately twice the expression level seen in T cells, B cells, and monocytes [saito-2021-neutrophils-abstract]. This neutrophil-predominant expression is consistent across tissue microenvironments, being observed in neutrophils from bone marrow, spleen, peripheral blood, liver, and kidney [saito-2021-neutrophils-abstract].

Within the T cell lineage, RASAL3 expression shows dynamic regulation during development. Expression is highest in the thymus, decreases in CD4+CD8+ double-positive thymocytes, then peaks again in CD4 and CD8 single-positive cells. Expression decreases once more in mature peripheral T cells [ishihara-2015-tcell-survival-abstract]. This developmental pattern suggests that RASAL3 may play stage-specific roles in T cell maturation and function.

The biological functions of RASAL3 in immune cells have been characterized through studies of RASAL3-deficient mice. In T cells, RASAL3 is dispensable for thymic development—RASAL3 knockout mice show normal T cell development in the thymus even when tested with TCR transgenic models [ishihara-2015-tcell-survival-abstract]. However, RASAL3 is essential for maintaining peripheral naive T cell populations. RASAL3-deficient mice exhibit significantly reduced numbers of naive CD4+ and CD8+ T cells (but not effector memory T cells) in peripheral lymphoid organs, accompanied by increased apoptosis of these cells [ishihara-2015-tcell-survival-abstract][muro-2018-tcell-inflammatory-abstract]. The survival defect is evident in vivo (by adoptive transfer experiments) but not in vitro in IL-7-supplemented cultures, suggesting RASAL3's survival function relates to tonic TCR signaling rather than cytokine-dependent survival pathways [ishihara-2015-tcell-survival-abstract].

In NKT cells, RASAL3 plays a critical role in cellular expansion and function. RASAL3-deficient mice exhibit a severe decrease in liver NKT cell numbers by 8 weeks of age [saito-2015-nkt-cells-abstract]. Functionally, RASAL3 deficiency results in reduced cytokine production (IL-4 and IFN-γ) following stimulation with the NKT cell agonist α-galactosylceramide, and these mice are protected from α-GalCer-induced liver injury [saito-2015-nkt-cells-abstract].

In neutrophils, RASAL3 functions as a critical negative regulator of inflammatory responses. RASAL3 expression is upregulated (5-15 fold) when neutrophils encounter inflammatory stimuli such as LPS, PMA, or heat-killed bacteria [saito-2021-neutrophils-abstract]. In the absence of RASAL3, neutrophils display augmented inflammatory responses including increased cytokine production (IL-1β, TNF-α, IL-6), enhanced reactive oxygen species generation, and elevated formation of neutrophil extracellular traps (NETs) [saito-2021-neutrophils-abstract].

A striking and somewhat paradoxical observation is that RASAL3 deficiency produces divergent effects in different hematopoietic cell lineages [saito-2021-neutrophils-abstract]. While RASAL3 loss results in reduced numbers and impaired survival of lymphocytes (T cells, NKT cells), it leads to increased numbers of neutrophils and granulocytes in the bone marrow with enhanced pro-inflammatory effector functions [mgi-rasal3-ortholog-summary][saito-2021-neutrophils-abstract]. This cell type-specific divergence suggests that identical perturbations in Ras signaling can produce opposite biological outcomes depending on the cellular context, likely reflecting differences in downstream signaling pathway architecture and transcriptional responses between lymphoid and myeloid lineages. Understanding the mechanistic basis for these discordant effects remains an important area for future investigation.

7. Disease Associations and Therapeutic Implications

The loss of RASAL3 function has been linked to several disease-relevant phenotypes, particularly those involving dysregulated inflammation. RASAL3-knockout mice demonstrate accelerated mortality in a septic shock model, with 100% mortality by 48 hours compared to approximately 40% mortality in wild-type controls [saito-2021-neutrophils-abstract]. This increased susceptibility is associated with severe hepatic necrosis and exaggerated systemic inflammation driven by hyperactivated neutrophils [saito-2021-neutrophils-abstract].

Clinically relevant to human disease, neutrophils from patients with sickle cell disease exhibit suppressed RASAL3 expression upon LPS activation, correlating with enhanced inflammatory responses and increased sepsis susceptibility [saito-2021-neutrophils-abstract]. Given that sepsis is a major cause of mortality in sickle cell disease patients, the decreased RASAL3 expression in these cells may contribute to their heightened inflammatory state and increased infection-related mortality [saito-2021-neutrophils-abstract]. These findings suggest that RASAL3 agonists could represent a novel therapeutic approach for managing excessive inflammation in sepsis and other hyperinflammatory conditions [saito-2021-neutrophils-abstract].

In the context of autoimmune and inflammatory diseases, RASAL3 deficiency has complex and somewhat paradoxical effects. Mice lacking RASAL3 show protection against neuroinflammation in experimental autoimmune encephalomyelitis (EAE) and experimental cerebral malaria (ECM) models [olivier-2024-ccdc88b-abstract]. However, these same mice display enhanced susceptibility to DSS-induced colitis and increased colorectal cancer development [olivier-2024-ccdc88b-abstract]. Similarly, RASAL3-deficient mice show ameliorated Th1- and Th2-dependent contact hypersensitivity reactions due to reduced T cell numbers [muro-2018-tcell-inflammatory-abstract]. These observations highlight the dual nature of RASAL3 function: its loss can be protective in certain inflammatory contexts (by reducing T cell-mediated inflammation) while being detrimental in others (by promoting neutrophil-mediated hyperinflammation or compromising barrier immunity).

Despite the general role of RasGAP proteins as tumor suppressors (NF1, RASAL1, RASAL2, and DAB2IP have established tumor suppressor functions), the evidence for RASAL3 as a cancer gene is currently limited [simanshu-2017-rasgaps-review-abstract][omim-616561-rasal3-summary]. According to the Cancer Gene Census (COSMIC), RASAL3 is not classified as a known cancer gene, and mouse insertional mutagenesis experiments do not support its designation as a cancer-causing gene [omim-616561-rasal3-summary]. This is notable given the hematopoietic-restricted expression of RASAL3, which would theoretically position it as a candidate tumor suppressor in hematological malignancies. However, the discovery that RASAL3 can regulate Rac2 GTPase activity has implications for Philadelphia chromosome-positive leukemias, where BCR-ABL directly activates Rac2 to promote cell survival through AKT signaling [tomida-2018-rac2-abstract]. RASAL3 may therefore function as a negative regulator of Rac2-AKT survival signaling in these leukemias, though this hypothesis requires direct experimental validation.

The Human Protein Atlas indicates that RASAL3 shows limited expression in most solid tumors, consistent with its hematopoietic tissue specificity [human-protein-atlas-rasal3-summary]. Some non-Hodgkin lymphomas show moderate cytoplasmic RASAL3 positivity, though the functional significance of this expression in lymphoma biology remains unexplored [human-protein-atlas-rasal3-summary]. The lack of established cancer associations may reflect the specialized nature of RASAL3 in immune cell function rather than general cell cycle control.

8. Open Questions

Despite significant progress in understanding RASAL3 function, several important questions remain unanswered:

Substrate Specificity: While RASAL3 has been shown to act on Ras and Rac2 in vitro, the relative contributions of these two activities to RASAL3's biological functions in vivo remain unclear. Are there cellular contexts where one activity predominates over the other? Does RASAL3 exhibit differential activity toward the three major Ras isoforms (HRAS, KRAS, NRAS)?

Regulatory Mechanisms: How is RASAL3 activity regulated? The mechanisms controlling RASAL3 membrane recruitment, GAP activity, and protein stability remain largely unexplored. Does calcium binding to the C2 domain regulate RASAL3 function as it does for other C2 domain-containing GAPs?

Structural Biology: No crystal structure of RASAL3 has been reported. Structural studies would provide insights into the basis for its substrate specificity and inform the design of potential therapeutic modulators.

Cancer Role: Does RASAL3 function as a tumor suppressor in hematological malignancies? Are RASAL3 mutations or epigenetic silencing observed in leukemias or lymphomas? What is the functional significance of RASAL3 expression in lymphomas?

Therapeutic Development: Can RASAL3 be targeted therapeutically? Would RASAL3 agonists be beneficial in sepsis and hyperinflammatory conditions? Could RASAL3 inhibitors be useful in conditions where enhanced immune cell function is desired?

Dendritic Cell Function: The recent discovery of RASAL3's role in dendritic cell migration through RhoA regulation opens new questions. How does RASAL3 integrate its Ras-GAP and RhoA-regulatory activities? Is Rac2 also involved in this context?

NKT Cell Biology: Why does RASAL3 deficiency specifically affect liver NKT cells? What is the mechanism by which RASAL3 regulates NKT cell expansion and cytokine production?

Human Genetics: Are there human genetic variants in RASAL3 associated with immune disorders, inflammatory diseases, or hematological malignancies? Population-scale genetic studies may reveal disease associations.

References

• [ishihara-2015-tcell-survival-abstract] Ishihara S, Fujita M, Takenaka-Ishikawa S, Tamura M, Koyama Y, Kawamura T, et al. (2015) The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells. PLoS ONE 10(3): e0119898. PMID: 25793935. PMCID: PMC4368693. DOI: 10.1371/journal.pone.0119898. URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119898

• [saito-2015-nkt-cells-abstract] Saito S, Kawamura T, Higuchi M, Kobayashi T, Yoshita-Takahashi M, Yamazaki M, et al. (2015) RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells. European Journal of Immunology 45(5):1512-23. PMID: 25652366. DOI: 10.1002/eji.201444977. URL: https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201444977

• [saito-2021-neutrophils-abstract] Saito S, Cao DY, Victor AR, Peng Z, Wu HY, Okwan-Duodu D (2021) RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils. Frontiers in Immunology 12:744300. PMID: 34777356. PMCID: PMC8579101. DOI: 10.3389/fimmu.2021.744300. URL: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.744300/full

• [muro-2018-tcell-inflammatory-abstract] Muro R, Nitta T, Kitajima M, Okada T, Suzuki H (2018) Rasal3-mediated T cell survival is essential for inflammatory responses. Biochemical and Biophysical Research Communications 496(1):25-30. PMID: 29291408. DOI: 10.1016/j.bbrc.2017.12.159. URL: https://pubmed.ncbi.nlm.nih.gov/29291408/

• [olivier-2024-ccdc88b-abstract] Olivier JF, Langlais D, et al. (2024) CCDC88B interacts with RASAL3 and ARHGEF2 and regulates dendritic cell function in neuroinflammation and colitis. Communications Biology 7(1):77. PMID: 38200184. PMCID: PMC10781698. DOI: 10.1038/s42003-023-05751-9. URL: https://www.nature.com/articles/s42003-023-05751-9

• [tomida-2018-rac2-abstract] Tomida S, Saito S, Kitagawa M (2018) RASAL3 preferentially stimulates GTP hydrolysis of the Rho family small GTPase Rac2. Biomedical Reports 9(3):255-260. PMCID: PMC6158391. DOI: 10.3892/br.2018.1119. URL: https://www.spandidos-publications.com/10.3892/br.2018.1119

• [simanshu-2017-rasgaps-review-abstract] Simanshu DK, Nissley DV, McCormick F (2017) Ras-Specific GTPase-Activating Proteins—Structures, Mechanisms, and Interactions. Cold Spring Harbor Perspectives in Medicine 9(3):a031500. PMID: 28620452. PMCID: PMC6396337. DOI: 10.1101/cshperspect.a031500. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC6396337/

• [human-protein-atlas-rasal3-summary] The Human Protein Atlas - RASAL3 (ENSG00000105122). URL: https://www.proteinatlas.org/ENSG00000105122-RASAL3

• [ncbi-gene-rasal3] NCBI Gene: RASAL3 RAS protein activator like 3 [Homo sapiens (human)] - Gene ID: 64926. URL: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=64926

• [omim-616561-rasal3-summary] OMIM Entry - *616561 - RAS PROTEIN ACTIVATOR-LIKE 3; RASAL3. URL: https://omim.org/entry/616561

• [genecards-rasal3] GeneCards - RASAL3 Gene. URL: https://www.genecards.org/cgi-bin/carddisp.pl?gene=RASAL3

• [mgi-rasal3-ortholog-summary] Mouse Genome Informatics - Rasal3 (MGI:2444128). URL: https://www.informatics.jax.org/marker/MGI:2444128

Citations

1. human-protein-atlas-rasal3-summary.md
2. ishihara-2015-tcell-survival-abstract.md
3. mgi-rasal3-ortholog-summary.md
4. muro-2018-tcell-inflammatory-abstract.md
5. olivier-2024-ccdc88b-abstract.md
6. omim-616561-rasal3-summary.md
7. saito-2015-nkt-cells-abstract.md
8. saito-2021-neutrophils-abstract.md
9. simanshu-2017-rasgaps-review-abstract.md
10. tomida-2018-rac2-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan
- Verified identity and domains: RASAL3 (UniProt Q86YV0), human, RasGAP-like protein with PH, C2, and RasGAP domains; aligned with literature.
- Collected and synthesized recent primary evidence (2024–2015) on function, pathways, cell types, and phenotypes.
- Summarized biochemical activity and substrate specificity; cellular localization and context; signaling roles; genetic/functional perturbation phenotypes; disease links and translational implications; and 2023–2024 developments.

Comprehensive Research Report: Human RASAL3 (UniProt Q86YV0)

1) Key concepts and definitions with current understanding
- Identity and domains: RASAL3 (RAS protein activator like-3) is a Ras-superfamily GTPase-activating protein (GAP) with an N‑terminal PH domain, a C2 domain, and a central RasGAP domain. This architecture matches the UniProt domain annotations and is consistent with experimental reports classifying RASAL3 within SynGAP-like RasGAPs predominantly expressed in hematopoietic lineages (human and mouse orthologs studied) (molecular domain descriptions and lineage expression summarized in Muro 2015; domain boundaries and annotations in human transcripts described in a clinical genetics report) (muro2015therasgtpaseactivating pages 1-2, iezziUnknownyearimplicationsofrasal3 pages 9-11).
- Biochemical function: RASAL3 accelerates GTP hydrolysis on small GTPases. In T cells, Rasal3 acts as a RasGAP to dampen Ras‑ERK signaling following TCR stimulation; it does not exhibit Rap1GAP activity in those assays (Muro 2015) (muro2015therasgtpaseactivating pages 1-2). In vitro GAP assays using human RASAL3 GAP domain found preferential stimulation of GTP hydrolysis on Rac2 (a hematopoietic Rho family GTPase), indicating substrate breadth beyond Ras and suggesting pathway crosstalk into Rac2–AKT signaling (Shin 2018) (shin2018rasal3preferentiallystimulates pages 2-3).
- Cellular context and complexes: In dendritic cells (DCs), RASAL3 physically and functionally associates with the scaffold CCDC88B and the Rho/Rac GEF ARHGEF2, forming a complex that modulates RHOA activation and cell migration (Olivier 2024, Communications Biology, Jan 2024, https://doi.org/10.1038/s42003-023-05751-9) (olivier2024ccdc88binteractswith pages 1-2).

2) Recent developments and latest research (prioritizing 2023–2024)
- DC migration and neuroinflammation/colitis models: A 2024 study identified CCDC88B–RASAL3–ARHGEF2 interactions and showed that loss of Rasal3 alters disease phenotypes in murine neuroinflammation (EAE protection) and colitis susceptibility. Mechanistically, the complex tunes DC migration via RHOA activity, with RASAL3 acting in an opposing fashion to ARHGEF2 (Olivier 2024; Jan 2024) (olivier2024ccdc88binteractswith pages 1-2).
- Integrative immunology context: Earlier multi-omics work from the same group leading up to 2024 situated RASAL3 in pathways controlling leukocyte mobility and inflammatory responses across myeloid and lymphoid compartments, linking Ras/ERK and Rac-family nodes; this provided the rationale for the 2024 focused mechanistic work (Olivier 2022) (olivier2022uncoveringnewimmunologicala pages 128-133).

3) Current applications and real-world implementations
- Immuno-inflammatory modulation: Mouse data indicate that RASAL3 restrains excessive neutrophil activation during sepsis, suggesting a potential target for limiting hyperinflammation. Rasal3 knockout enhanced mortality in LPS-induced septic shock and increased neutrophil effector responses, positioning RASAL3 as a negative regulator of neutrophil-driven pathology (Saito 2021, Frontiers in Immunology, Oct 2021, https://doi.org/10.3389/fimmu.2021.744300) (saito2021rasal3isa pages 2-3).
- Adaptive immunity homeostasis: In vivo maintenance of naive T cell pools requires Rasal3; loss reduces peripheral naive CD4+ and CD8+ T cells by increasing apoptosis, highlighting a role in tonic signaling and homeostatic survival relevant to immune reconstitution and tolerance (Muro 2015, PLoS ONE, Mar 2015, https://doi.org/10.1371/journal.pone.0119898) (muro2015therasgtpaseactivating pages 2-4, muro2015therasgtpaseactivating pages 1-2).
- DC migration and disease modulation: The 2024 work implies that manipulating the CCDC88B–RASAL3–ARHGEF2 axis could modulate DC trafficking and antigen presentation, with implications for neuroinflammation and intestinal inflammation interventions (Olivier 2024) (olivier2024ccdc88binteractswith pages 1-2).

4) Expert opinions and analysis from authoritative sources
- The 2024 Communications Biology study provides peer‑reviewed mechanistic evidence positioning RASAL3 in a defined protein complex that controls DC migration via RHOA. The authors interpret opposing actions of ARHGEF2 (activator) and RASAL3 (inhibitory context) within the complex to explain differential DC motility and disease outcomes in mice (Olivier 2024; Jan 2024) (olivier2024ccdc88binteractswith pages 1-2).
- Foundational T cell work by Muro et al. proposes Rasal3 as a selective RasGAP in T cells that limits TCR‑driven ERK signaling, thereby supporting naive T cell survival; this interpretation remains widely cited in immunology for RasGAP functional diversity in T cells (Muro 2015) (muro2015therasgtpaseactivating pages 1-2).
- Biochemical expansion to Rac2 by Shin et al. suggests RASAL3’s GAP activity can impact Rho‑family GTPase signaling in hematopoietic cells, an interpretation that is congruent with the DC migration findings involving RHOA pathway modulation (Shin 2018) (shin2018rasal3preferentiallystimulates pages 2-3).

5) Relevant statistics and data from recent studies
- DC/Inflammation (2024): The Communications Biology paper reports generation and validation of Arhgef2 and Rasal3 mutants, and demonstrates differential DC migration phenotypes in vitro; Rasal3 mutants show enhanced DC migration, aligning with reduced neuroinflammation in EAE and altered DSS‑colitis susceptibility in vivo (details and figures in paper; Jan 2024) (olivier2024ccdc88binteractswith pages 1-2).
- Neutrophil inflammation (2021): In LPS (5 mg/kg) models, Rasal3 knockout mice exhibited significantly increased mortality through hyperinflammation and organ damage; RASAL3 was upregulated by exogenous neutrophil stimuli and functioned to limit NETosis and inflammatory outputs (Frontiers in Immunology, Oct 2021) (saito2021rasal3isa pages 2-3).
- T cell survival (2015): Rasal3-deficient mice had significantly reduced numbers of peripheral naive CD4+ and CD8+ T cells due to increased apoptosis; TCR‑ERK phosphorylation was repressed by Rasal3 in cell lines, and RasGAP activity (but not Rap1GAP) confirmed with pulldown assays (PLoS ONE, Mar 2015) (muro2015therasgtpaseactivating pages 2-4, muro2015therasgtpaseactivating pages 1-2).
- Biochemical specificity (2018): In vitro GAP assays showed human RASAL3 GAP domain preferentially accelerates Rac2 GTP hydrolysis compared to other Rho/Ras family members tested (Biomedical Reports, Jul 2018) (shin2018rasal3preferentiallystimulates pages 2-3).

Focused mechanistic narrative
- Biochemical activity and substrate specificity: RASAL3 is a GAP that inactivates Ras in T cells (no Rap1GAP activity detected in those assays) and can directly stimulate GTP hydrolysis on Rac2 in vitro, indicating dual potential targets within Ras and Rho subfamilies relevant to hematopoietic signaling (Muro 2015; Shin 2018) (muro2015therasgtpaseactivating pages 1-2, shin2018rasal3preferentiallystimulates pages 2-3).
- Signaling roles and pathways: In T cells, Rasal3 dampens TCR‑induced Ras→Raf→MEK→ERK signaling, supporting naive T cell survival. In myeloid cells, RASAL3 modulates inflammatory outputs; in DCs, it participates in a CCDC88B–RASAL3–ARHGEF2 complex that tunes RHOA activity and migration, placing RASAL3 at the intersection of Ras‑ERK and Rho‑GTPase circuits (Muro 2015; Saito 2021; Olivier 2024) (muro2015therasgtpaseactivating pages 1-2, saito2021rasal3isa pages 2-3, olivier2024ccdc88binteractswith pages 1-2).
- Interacting partners and complexes: CCDC88B (scaffold) and ARHGEF2 (Rho/Rac GEF) physically and functionally interact with RASAL3 in DCs, with opposing regulatory effects on migration via RHOA modulation (Olivier 2024) (olivier2024ccdc88binteractswith pages 1-2).

Expression pattern and localization
- Hematopoietic bias: RASAL3 is predominantly expressed in T‑lineage cells and other hematopoietic cells, including neutrophils; neutrophil expression increases with exogenous inflammatory stimuli (Muro 2015; Saito 2021) (muro2015therasgtpaseactivating pages 1-2, saito2021rasal3isa pages 2-3).
- Subcellular behavior: Consistent with PH/C2 domains, RASAL3 is suited for membrane-proximal signaling; in DCs it colocalizes within complexes (confocal IF) with CCDC88B/ARHGEF2 that regulate migration, implying function at or near signaling membranes controlling RHOA activity (Olivier 2024) (olivier2024ccdc88binteractswith pages 1-2).

Loss-/gain-of-function phenotypes in cells and mice
- T cells: Rasal3 knockout mice retain normal thymic selection but lose peripheral naive T cells due to impaired in vivo survival; Rasal3 represses TCR‑induced ERK phosphorylation (Muro 2015) (muro2015therasgtpaseactivating pages 2-4, muro2015therasgtpaseactivating pages 1-2).
- NKT cells: Prior work reported reduced NKT cell numbers and cytokine production with Rasal3 perturbation, implicating Rasal3 in NKT-mediated responses (European Journal of Immunology; 2015; DOI cited in the literature synthesis) (olivier2022uncoveringnewimmunologicala pages 128-133).
- Neutrophils: Rasal3 deficiency enhances neutrophil activation and increases sepsis mortality; RASAL3 expression is induced by inflammatory stimuli (Saito 2021) (saito2021rasal3isa pages 2-3).
- Dendritic cells: Rasal3 mutant DCs show enhanced migration/motility; loss of Rasal3 dampens neuroinflammation and alters colitis susceptibility in vivo (Olivier 2024) (olivier2024ccdc88binteractswith pages 1-2).

Disease associations and translational implications
- Autoimmunity: A clinical genetics report describes deleterious RASAL3 variants identified by whole‑exome sequencing in pediatric autoimmune cohorts (e.g., Evans syndrome, autoimmune hepatitis), suggesting a role in immune tolerance; while details require further validation, the association flags RASAL3 for diagnostic consideration in immune dysregulation (report with gene mapping and domain annotation) (iezziUnknownyearimplicationsofrasal3a pages 9-11, iezziUnknownyearimplicationsofrasal3 pages 9-11).
- Infection and sepsis: RASAL3 restrains neutrophil hyperinflammation; deficiency exacerbates endotoxin shock mortality, nominating RASAL3 signaling as a potential therapeutic axis to mitigate harmful innate immune overactivation (Saito 2021) (saito2021rasal3isa pages 2-3).
- Neuroinflammation and colitis: The DC migration role of RASAL3 impacts disease severity in EAE and DSS models, positioning the CCDC88B–RASAL3–ARHGEF2 hub as a candidate for modulating antigen-presenting cell trafficking and tissue inflammation (Olivier 2024) (olivier2024ccdc88binteractswith pages 1-2).
- Epigenetic regulation: Prior reviews have suggested RASGAP genes, including RASAL3, can be transcriptionally or epigenetically controlled in cancer and immune contexts; while specific RASAL3 methylation data were not directly quantified in the curated sources here, its immune-restricted expression and inducibility imply context-dependent regulation that warrants targeted epigenomic profiling (synthesis from collected context) (olivier2022uncoveringnewimmunologicala pages 128-133).

2023–2024 highlights
- Definitive complex and mechanism in DCs (CCDC88B–RASAL3–ARHGEF2) with RHOA modulation and migration control; disease phenotypes in EAE/colitis models (Communications Biology, Jan 2024; https://doi.org/10.1038/s42003-023-05751-9) (olivier2024ccdc88binteractswith pages 1-2).
- Expanded systems context for RASAL3 across myeloid/lymphoid inflammation (Olivier 2022 integrative work leading to 2024 study) (olivier2022uncoveringnewimmunologicala pages 128-133).

Verification of target identity and domain alignment
- The research cited here consistently examines RASAL3 as “RAS protein activator like‑3,” human and mouse orthologs, with PH, C2 and RasGAP domains, matching UniProt Q86YV0 annotations. No conflicting gene symbol usage was found; all studies align with hematopoietic/immune contexts and Ras/Rho GTPase regulation (Muro 2015; Shin 2018; Olivier 2024) (muro2015therasgtpaseactivating pages 1-2, shin2018rasal3preferentiallystimulates pages 2-3, olivier2024ccdc88binteractswith pages 1-2).

Limitations and open questions
- Direct structural determinations for human RASAL3 domains and in‑cell substrate specificities remain limited; while T cell assays support RasGAP activity and in vitro assays show Rac2 preference, in vivo substrate engagement likely depends on cell type, membrane localization, and interacting partners (muro2015therasgtpaseactivating pages 1-2, shin2018rasal3preferentiallystimulates pages 2-3, olivier2024ccdc88binteractswith pages 1-2).
- Human genetic evidence for autoimmunity association requires larger cohorts and functional validation of specific variants (iezziUnknownyearimplicationsofrasal3a pages 9-11, iezziUnknownyearimplicationsofrasal3 pages 9-11).

Embedded summary of key studies
| Year | Study (first author, journal) | Species / Model | Cell type / context | Key finding (function / pathway) | Notable methods | URL / DOI |
|------|--------------------------------|-----------------|---------------------|-----------------------------------|-----------------|-----------|
| 2024 | Olivier J-F, Communications Biology | Mouse (Rasal3 / Arhgef2 mutants) | Dendritic cells; immune tissues | RASAL3 physically interacts with CCDC88B and ARHGEF2; regulates DC migration via modulation of RHOA and impacts neuroinflammation and DSS-colitis susceptibility (CCDC88B–RASAL3–ARHGEF2 complex) | Proteomics, co-immunoprecipitation, confocal IF, KO mice, EAE and DSS models (migration assays) | https://doi.org/10.1038/s42003-023-05751-9 (olivier2024ccdc88binteractswith pages 1-2) |
| 2022 | Olivier JF, "Uncovering New Immunological Pathways" (report) | Murine models / immune cells | Myeloid cells, T cells, DCs | Places RASAL3 in complexes regulating leukocyte mobility and inflammatory responses; links to Ras/ERK and Rac2 signaling in immune cells | Transcriptomics / proteomics in murine inflammation models | N/A (olivier2022uncoveringnewimmunologicala pages 128-133) |
| 2021 | Saito S., Frontiers in Immunology | Mouse (RASAL3-KO C57BL/6J) | Neutrophils | RASAL3 is a RasGAP highly expressed in neutrophils; restrains neutrophil hyperactivation and excessive inflammation; Rasal3-KO mice show increased mortality in LPS sepsis | KO mouse model, LPS-induced sepsis, neutrophil isolation, NETosis and functional assays | https://doi.org/10.3389/fimmu.2021.744300 (saito2021rasal3isa pages 2-3) |
| 2018 | Shin Y., Biomedical Reports | In vitro / human proteins | Hematopoietic-relevant GTPases (Rac2) | RASAL3 GAP domain preferentially stimulates GTP hydrolysis of Rac2 (Rho family), suggesting Rac2 as a substrate and linking RASAL3 to Rac2-AKT signaling in hematopoietic cells | Purified protein GAP assays, GST/FLAG constructs, transfected HEK293 lysates | https://doi.org/10.3892/br.2018.1119 (shin2018rasal3preferentiallystimulates pages 2-3) |
| 2015 | Muro R., PLoS ONE | Mouse (Rasal3-deficient) | T cells (naive CD4+/CD8+) | RASAL3 possesses RasGAP (not Rap1GAP) activity; represses TCR-stimulated ERK phosphorylation and is required for in vivo survival of peripheral naive T cells | KO mouse, adoptive transfer, Raf1-RBD / RalGDS pulldown assays, flow cytometry | https://doi.org/10.1371/journal.pone.0119898 (muro2015therasgtpaseactivating pages 2-4) |
| 2015 | Saito S., European Journal of Immunology (NKT study) | Mouse models | NKT cells | RASAL3 regulates number and function of NKT cells and influences cytokine production and NKT-mediated immune responses (reported in EJI) | KO mice, flow cytometry, functional cytokine assays | https://doi.org/10.1002/eji.201444977 (olivier2022uncoveringnewimmunologicala pages 128-133) |
| Unknown (WES report) | Iezzi S., Implications of RASAL3 gene mutations (unknown journal) | Human (clinical WES cohorts) | Pediatric autoimmune cohorts (clinical samples) | Reports deleterious RASAL3 variants in pediatric autoimmune cases (e.g., Evans syndrome, autoimmune hepatitis), implicating RASAL3 in loss of immune tolerance | Whole-exome sequencing and variant annotation in patient cohorts | N/A (iezziUnknownyearimplicationsofrasal3a pages 9-11) |
| 2023–2024 | Pan-cancer / review summaries (multiple) | Human cancer datasets / transcriptomes | Various tumors; tumor immune microenvironment | RASAL3 appears in transcriptomic analyses tied to immune infiltration/prognosis in some cancers and is discussed in reviews of RASGAPs' roles in cancer immunity and tumor microenvironment regulation | Bioinformatics, pan-cancer expression and survival analyses (review synthesis) | Representative review / analyses cited in collected evidence (olivier2022uncoveringnewimmunologicala pages 128-133) |

Table: Concise table summarizing primary and recent studies on RASAL3 (human/mouse), listing models, cell contexts, main functional findings, methods, and DOIs/URLs; useful for rapid literature orientation and citation (context IDs shown).

References with URLs and dates
- Olivier J‑F et al. CCDC88B interacts with RASAL3 and ARHGEF2 and regulates dendritic cell function in neuroinflammation and colitis. Communications Biology. Published Jan 2024. URL: https://doi.org/10.1038/s42003-023-05751-9 (olivier2024ccdc88binteractswith pages 1-2).
- Olivier JF. Uncovering New Immunological Pathways Driving Inflammatory Response of Myeloid Cells in Murine Models of Neuroinflammation and Colitis. 2022. Contextual report linking RASAL3 to leukocyte mobility and inflammation (olivier2022uncoveringnewimmunologicala pages 128-133).
- Saito S et al. RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils. Frontiers in Immunology. Published Oct 2021. URL: https://doi.org/10.3389/fimmu.2021.744300 (saito2021rasal3isa pages 2-3).
- Muro R et al. The Ras GTPase‑Activating Protein Rasal3 Supports Survival of Naive T Cells. PLoS ONE. Published Mar 2015. URL: https://doi.org/10.1371/journal.pone.0119898 (muro2015therasgtpaseactivating pages 2-4, muro2015therasgtpaseactivating pages 1-2).
- Shin Y et al. RASAL3 preferentially stimulates GTP hydrolysis of the Rho family small GTPase Rac2. Biomedical Reports. Published Jul 2018. URL: https://doi.org/10.3892/br.2018.1119 (shin2018rasal3preferentiallystimulates pages 2-3).
- Iezzi S. Implications of RASAL3 gene mutations in autoimmune diseases (clinical genetics summary; year/journal not specified in excerpt). Provides ENST mapping, domain annotation, and WES observations in pediatric autoimmune cohorts (iezziUnknownyearimplicationsofrasal3a pages 9-11, iezziUnknownyearimplicationsofrasal3 pages 9-11).

Citations for major claims are provided inline throughout this report using context IDs (see parentheses).

References

1. (muro2015therasgtpaseactivating pages 1-2): Ryunosuke Muro, Takeshi Nitta, Toshiyuki Okada, Hitoshi Ideta, Takeshi Tsubata, and Harumi Suzuki. The ras gtpase-activating protein rasal3 supports survival of naive t cells. PLoS ONE, 10:e0119898, Mar 2015. URL: https://doi.org/10.1371/journal.pone.0119898, doi:10.1371/journal.pone.0119898. This article has 31 citations and is from a peer-reviewed journal.

2. (iezziUnknownyearimplicationsofrasal3 pages 9-11): S IEZZI. Implications of rasal3 gene mutations in autoimmune diseases. Unknown journal, Unknown year.

3. (shin2018rasal3preferentiallystimulates pages 2-3): Yoonjae Shin, Yong Woo Kim, Hye-Ran Kim, Nakyoung Shin, Tae Sung Kim, T. Kwon, J. Choi, and Jongsoo Chang. Rasal3 preferentially stimulates gtp hydrolysis of the rho family small gtpase rac2. Biomedical reports, 9 3:241-246, Jul 2018. URL: https://doi.org/10.3892/br.2018.1119, doi:10.3892/br.2018.1119. This article has 6 citations and is from a peer-reviewed journal.

4. (olivier2024ccdc88binteractswith pages 1-2): Jean-Frederic Olivier, David Langlais, Thiviya Jeyakumar, Maria J. Polyak, Luc Galarneau, Romain Cayrol, Hua Jiang, Kelly R. Molloy, Guoyue Xu, Harumi Suzuki, John LaCava, Philippe Gros, and Nassima Fodil. Ccdc88b interacts with rasal3 and arhgef2 and regulates dendritic cell function in neuroinflammation and colitis. Communications Biology, Jan 2024. URL: https://doi.org/10.1038/s42003-023-05751-9, doi:10.1038/s42003-023-05751-9. This article has 8 citations and is from a peer-reviewed journal.

5. (olivier2022uncoveringnewimmunologicala pages 128-133): JF Olivier. Uncovering new immunological pathways driving inflammatory response of myeloid cells in murine models of neuroinflammation and colitis. Unknown journal, 2022.

6. (saito2021rasal3isa pages 2-3): Suguru Saito, Duo-Yao Cao, Aaron R. Victor, Zhenzi Peng, Hui-Ya Wu, and Derick Okwan-Duodu. Rasal3 is a putative rasgap modulating inflammatory response by neutrophils. Frontiers in Immunology, Oct 2021. URL: https://doi.org/10.3389/fimmu.2021.744300, doi:10.3389/fimmu.2021.744300. This article has 18 citations and is from a peer-reviewed journal.

7. (muro2015therasgtpaseactivating pages 2-4): Ryunosuke Muro, Takeshi Nitta, Toshiyuki Okada, Hitoshi Ideta, Takeshi Tsubata, and Harumi Suzuki. The ras gtpase-activating protein rasal3 supports survival of naive t cells. PLoS ONE, 10:e0119898, Mar 2015. URL: https://doi.org/10.1371/journal.pone.0119898, doi:10.1371/journal.pone.0119898. This article has 31 citations and is from a peer-reviewed journal.

8. (iezziUnknownyearimplicationsofrasal3a pages 9-11): S IEZZI. Implications of rasal3 gene mutations in autoimmune diseases. Unknown journal, Unknown year.

Citations

1. muro2015therasgtpaseactivating pages 1-2
2. olivier2022uncoveringnewimmunologicala pages 128-133
3. muro2015therasgtpaseactivating pages 2-4
4. https://doi.org/10.1038/s42003-023-05751-9
5. https://doi.org/10.3389/fimmu.2021.744300
6. https://doi.org/10.1371/journal.pone.0119898
7. https://doi.org/10.3892/br.2018.1119
8. https://doi.org/10.1002/eji.201444977
9. https://doi.org/10.1371/journal.pone.0119898,
10. https://doi.org/10.3892/br.2018.1119,
11. https://doi.org/10.1038/s42003-023-05751-9,
12. https://doi.org/10.3389/fimmu.2021.744300,

RASAL3 (Q86YV0) – Structure, Function, and Biological Role

Overview and Family Background

RASAL3 (Ras protein activator-like 3) is a member of the Ras GTPase-activating protein (RasGAP) family, proteins that function as key negative regulators of Ras signaling (www.ncbi.nlm.nih.gov). RasGAPs turn off Ras by accelerating the hydrolysis of Ras-bound GTP to GDP, thus terminating Ras signal transduction (pmc.ncbi.nlm.nih.gov). Human RASAL3 was identified in the mid-2010s as a novel RasGAP predominantly expressed in hematopoietic (blood/immune) cells (pubmed.ncbi.nlm.nih.gov). It is one of 14 known RasGAPs, which include RasGAP1 (p120 RasGAP/RASA1), neurofibromin (NF1), and other RASAL and RASA family members (pmc.ncbi.nlm.nih.gov). Like other RasGAPs, RASAL3 is thought to act as a tumor suppressor in the Ras pathway by keeping Ras activity in check (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). (The official human RASAL3 gene ID is 64926, and the UniProt accession is Q86YV0 (www.genecards.org).)

Protein Structure and Localization

RASAL3 encodes a cytosolic protein of ~748 amino acids that contains several important domains: an N-terminal pleckstrin homology (PH) domain, a C2 domain, and a C-terminal RasGAP domain (www.ncbi.nlm.nih.gov). This multi-domain architecture is characteristic of the synaptic RasGAP (SynGAP) subfamily to which RASAL3 belongs (pmc.ncbi.nlm.nih.gov). The PH domain typically binds phosphoinositides (lipids like PIP₂/PIP₃) in the plasma membrane, and the C2 domain often mediates calcium-dependent membrane association (pmc.ncbi.nlm.nih.gov). Indeed, sequence analysis suggested RASAL3 might translocate to the plasma membrane upon T-cell receptor (TCR) stimulation as a result of calcium influx and phosphatidylinositol (3,4,5)-trisphosphate generation (pmc.ncbi.nlm.nih.gov). In practice, RASAL3 has been observed to localize near or at the inner plasma membrane when overexpressed in cells (www.ncbi.nlm.nih.gov). However, one experimental study did not detect a rapid translocation of endogenous RASAL3 from cytosol to membrane after TCR signaling, implying that its membrane recruitment may be constitutive or require specific conditions not captured in that assay (pmc.ncbi.nlm.nih.gov). Overall, RASAL3 is a predicted intracellular protein (no signal peptide or transmembrane regions) and is thought to carry out its function at the cytoplasmic face of the plasma membrane, where it can interact with membrane-bound Ras GTPases (www.ncbi.nlm.nih.gov). Consistently, reducing RASAL3 levels causes accumulation of Ras in its active (GTP-bound) form, indicating RASAL3 normally functions at the membrane to inactivate Ras (www.ncbi.nlm.nih.gov).

RasGAP Enzymatic Activity and Specificity

The primary biochemical function of RASAL3 is to act as a Ras GTPase-activating protein, accelerating the conversion of Ras-GTP to Ras-GDP and thereby turning off Ras signaling (www.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In vitro enzymatic assays and cell-based studies confirm that RASAL3 possesses GAP activity toward Ras family GTPases (pmc.ncbi.nlm.nih.gov). For example, a 2015 study demonstrated that RASAL3 overexpression in T cells significantly enhanced the GTPase activity of Ras, leading to reduced phosphorylation of the downstream ERK kinase upon stimulation (pmc.ncbi.nlm.nih.gov). Notably, RASAL3 showed specificity for Ras and did not appreciably act on Rap1, a related small GTPase, indicating that its GAP activity is selective for Ras over certain other GTPases (pmc.ncbi.nlm.nih.gov). This substrate preference aligns with RASAL3’s role in modulating the Ras-MAPK pathway rather than the Rap1 pathway in T cells (pmc.ncbi.nlm.nih.gov).

Interestingly, emerging evidence suggests RASAL3 may also target Rac2, a small GTPase of the Rho family predominantly found in hematopoietic cells. In a 2018 biochemical study, Shin et al. found that the isolated GAP domain of RASAL3 could stimulate GTP hydrolysis by Rac2 in vitro, with little effect on Rac1 (pmc.ncbi.nlm.nih.gov). Rac2 is an important regulator of actin dynamics and reactive oxygen species in immune cells (especially neutrophils), and both Rac2 and RASAL3 are mainly expressed in hematopoietic lineages (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This finding raises the possibility that RASAL3 might have a dual specificity or a context-dependent GAP activity, functioning as a Rac2-selective GAP under certain conditions (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). However, Ras remains the principal substrate of RASAL3 in most studied contexts, and further research is needed to clarify how RASAL3’s interaction with Rac2 operates in cells. The prevailing view is that RASAL3 serves as a negative regulator of Ras signaling, given that reducing RASAL3 expression leads to elevated Ras-GTP levels and enhanced Ras pathway output (www.ncbi.nlm.nih.gov).

Role in Ras/ERK and Related Signaling Pathways

Ras signaling is a central pathway controlling cell proliferation, differentiation, and survival. When Ras is GTP-bound (active), it triggers multiple downstream cascades – most notably the RAF–MEK–ERK MAP kinase pathway – and can also engage PI3K–AKT and Rho family signaling branches (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). RASAL3, by turning Ras “off,” is a critical modulator of these pathways in cells where it is expressed. For instance, in T lymphocytes, RASAL3 acts to repress TCR-induced ERK phosphorylation, thereby fine-tuning the intensity of the MAPK signal following antigen recognition (pmc.ncbi.nlm.nih.gov). In the absence of RASAL3, TCR stimulation leads to abnormally prolonged or elevated ERK activation (pmc.ncbi.nlm.nih.gov), underscoring that RASAL3 sets a threshold for Ras-MAPK signaling in T cells.

Likewise, in innate immune cells such as neutrophils, RASAL3 restrains the Ras pathway to prevent excessive activation of downstream effectors like NF-κB, p38 MAPK, and AKT. A recent (2021) Frontiers in Immunology study showed that RASAL3-deficient neutrophils have higher levels of Ras-GTP and consequently hyper-activate multiple pathways: NF-κB p65, p38, and AKT were all significantly more upregulated in RASAL3-knockout neutrophils upon stimulation, compared to wild-type cells (pmc.ncbi.nlm.nih.gov). These signaling changes led to heightened production of pro-inflammatory cytokines and reactive oxygen species when RASAL3 was absent (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Thus, through its GAP activity, RASAL3 enforces negative feedback on Ras-dependent signaling axes (ERK/MAPK, PI3K/AKT, etc.), maintaining cellular responses within a proper range. When RASAL3 is lost, Ras signaling goes unchecked, resulting in amplified downstream responses (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This broad impact on Ras pathways explains many of the physiological consequences observed in RASAL3 loss-of-function models (from lymphocyte survival defects to inflammatory injury, detailed below).

Expression Profile and Cellular Localization

RASAL3 expression is highly tissue-specific, with strongest expression in the immune system. Transcript profiling indicates enriched expression in lymphoid organs (e.g. spleen, lymph nodes) and blood cell lineages (www.ncbi.nlm.nih.gov). RASAL3 is predominantly expressed by hematopoietic cells, including T cells, natural killer T (NKT) cells, B cells, and neutrophils (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In fact, among blood cell types, neutrophils appear to express RASAL3 at particularly high levels (pmc.ncbi.nlm.nih.gov), and T cells (especially naïve T cells) also show high RASAL3 expression (pmc.ncbi.nlm.nih.gov). The protein has multiple isoforms due to alternative splicing (www.ncbi.nlm.nih.gov), but all isoforms share the key functional domains described above. No signal peptide or extracellular domain is present, so RASAL3 resides inside the cell. It is generally classified as an intracellular, cytosolic protein that can associate with the inner leaflet of the plasma membrane (via PH/C2 domain interactions) where its substrate Ras is located (www.ncbi.nlm.nih.gov). Experimental overexpression of RASAL3 leads to a plasma membrane-localized pattern (www.ncbi.nlm.nih.gov), though endogenous RASAL3 may shuttle or partition between cytosol and membrane depending on cell state. Overall, RASAL3 carries out its function at the cytoplasmic face of the plasma membrane, interacting with membrane-anchored Ras GTPases and possibly other signaling proteins in that vicinity.

Biological Functions in Immune Cells

RASAL3 plays critical regulatory roles in various immune cell types by modulating Ras signaling thresholds. Research in mouse models has illuminated several key functions:

• T Cells (Naïve T Lymphocytes): RASAL3 is required for the survival of naïve T cells in the peripheral immune system. In a 2015 study, Muro et al. generated systemic Rasal3-knockout mice and found that while T cell development in the thymus was essentially normal, the peripheral pool of naïve T cells was markedly diminished (pmc.ncbi.nlm.nih.gov). Rasal3-deficient mice showed significantly reduced numbers of CD4⁺ and CD8⁺ naive T cells (with a corresponding increase in apoptosis of these cells), even though their effector/memory T cell counts were unaffected (pmc.ncbi.nlm.nih.gov). Adoptive transfer experiments confirmed that in vivo survival of Rasal3-deficient naive T cells was impaired, whereas their survival in vitro with IL-7 (a key T-cell survival cytokine) was normal (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These results suggest that RASAL3 helps naive T cells interpret homeostatic signals (likely weak TCR-self peptide interactions or cytokine cues) such that Ras/ERK activation is kept below a pro-apoptotic threshold (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Without RASAL3’s braking effect on Ras, naive T cells may receive too much basal Ras signaling, leading to activation-induced cell death or failure to compete for survival niches (pmc.ncbi.nlm.nih.gov). Collectively, RASAL3 ensures optimal T cell numbers in the periphery by preventing unwarranted Ras-driven signals that would otherwise cull the naive T cell population (pmc.ncbi.nlm.nih.gov).

• Natural Killer T (NKT) Cells: NKT cells are innate-like lymphocytes, and RASAL3 has an important role in their homeostasis and function. A 2015 immunology study identified RASAL3 as a hematopoietic-specific RasGAP and showed it is highly expressed in NKT cells (pubmed.ncbi.nlm.nih.gov). Mice lacking RASAL3 had a severe reduction of NKT cells in the liver (a key site for NKT cell residence) by 8 weeks of age (pubmed.ncbi.nlm.nih.gov). Moreover, when RASAL3-deficient mice were given α-Galactosylceramide (α-GalCer) – a glycolipid that specifically activates NKT cells – they exhibited attenuated liver injury compared to wild-type mice (pubmed.ncbi.nlm.nih.gov). This reduced tissue damage was linked to the fact that RASAL3-KO mice had far fewer NKT cells and that those NKT cells produced significantly lower levels of cytokines like IL-4 and IFN-γ upon activation (pubmed.ncbi.nlm.nih.gov). Mechanistically, NKT cells without RASAL3 showed hyper-activated ERK phosphorylation when stimulated (pubmed.ncbi.nlm.nih.gov), consistent with loss of a Ras pathway “off-switch.” The overall conclusion was that RASAL3 promotes the proper expansion and effector functions of NKT cells by negatively regulating Ras/ERK signaling (pubmed.ncbi.nlm.nih.gov). In other words, NKT cells require RASAL3-mediated Ras restraint to expand to normal numbers; excessive Ras activity (in the KO) seemingly impaired their proliferation or survival, leading to fewer NKT cells and dampened responses (pubmed.ncbi.nlm.nih.gov). This finding positions RASAL3 as a potential immune regulatory target, since modulating its activity could influence NKT cell–mediated immunity (for example, in NKT-driven diseases) (pubmed.ncbi.nlm.nih.gov).

• B Cells: RASAL3 is expressed in B lymphocytes as well (pubmed.ncbi.nlm.nih.gov), although detailed functional studies in B cells are not as well documented as for T and NKT cells. Given that Ras signaling also plays a role in B cell activation and development, it is likely that RASAL3 contributes to setting thresholds for B-cell receptor (BCR) signaling, perhaps analogous to its role in T cells. High RASAL3 expression in spleen and lymph nodes (which are rich in B cells) supports a role in the B lineage (www.ncbi.nlm.nih.gov). Some RasGAP family members (e.g. RASA1/p120 RasGAP) are known to regulate B cell development, but specific effects of RASAL3 in B cells remain to be fully elucidated. No major B-cell developmental defect was noted in the Rasal3 knockout mice reported by Muro et al., but further research is needed to clarify RASAL3’s influence on antibody-producing cells.

• Neutrophils and Inflammatory Response: Recent work has highlighted a crucial role for RASAL3 in neutrophils, the frontline innate immune cells. Saito et al. (2021) showed that RASAL3 is one of the most highly expressed Ras regulators in neutrophils and acts as an essential brake on neutrophil activation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). They observed that inflammatory stimuli (e.g. bacterial lipopolysaccharide, LPS) further upregulate RASAL3 expression in neutrophils, suggesting RASAL3 is induced as part of a feedback mechanism to prevent over-activation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In RASAL3 knockout mice, neutrophils responded to inflammatory triggers with exaggerated activation – producing more inflammatory cytokines (such as TNF-α) and more reactive oxygen species than normal (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This hyper-responsiveness had severe consequences: RASAL3-deficient mice succumbed to endotoxic septic shock much faster and at higher rates than wild-type mice (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In an LPS-induced sepsis model, 100% of Rasal3–KO mice died within 48 hours, whereas ~40% of wild-type mice were still alive at that time point (and ~20% of WT survived the full 72-hour observation period) (pmc.ncbi.nlm.nih.gov). The RASAL3-KO animals showed signs of uncontrolled “cytokine storm” and tissue damage in organs, consistent with neutrophil-driven hyperinflammation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Notably, a similar exacerbation of inflammation was seen in a sickle cell disease model, where neutrophils with low RASAL3 expression caused heightened inflammatory damage (pmc.ncbi.nlm.nih.gov). These results demonstrate that RASAL3 functions as a critical modulator of neutrophil activation, preventing excessive Ras-driven signaling that would otherwise lead to collateral tissue injury in inflammatory conditions (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). From a mechanistic perspective, Ras hyperactivity in RASAL3-null neutrophils led to stronger activation of downstream pathways (ERK, NF-κB, p38, Akt), fueling the overproduction of inflammatory mediators (pmc.ncbi.nlm.nih.gov). Thus, RASAL3 helps maintain immune homeostasis: it allows neutrophils to respond to infections effectively while curbing the potential for destructive inflammation.

In summary, across multiple immune cell types, RASAL3 acts as a checkpoint that restrains Ras-dependent signaling. This moderation is essential for normal immune cell development (ensuring cells like NKT and naïve T cells are neither over-stimulated nor eliminated) and for preventing immunopathology (avoiding excessive neutrophil activation and tissue damage). Its roles in T, NKT, and neutrophils highlight RASAL3’s broader function in fine-tuning immune responses via the Ras/MAPK pathway.

Pathways and Interactions

Beyond the Ras/ERK cascade, RASAL3’s activity can influence other signaling branches that intersect with Ras. For example, Ras activation can lead to PI3K–Akt signaling, and indeed in RASAL3-deficient neutrophils Akt phosphorylation was found to be elevated alongside ERK (pmc.ncbi.nlm.nih.gov). There is also crosstalk between Ras and Rho family GTPases in cytoskeletal dynamics; by potentially targeting Rac2 in hematopoietic cells, RASAL3 might link Ras and Rac pathways in certain contexts (pmc.ncbi.nlm.nih.gov). Moreover, RASAL3 might participate in multi-protein signaling complexes. A recent proteomics study in multiple myeloma cells discovered that RASAL3 physically interacts with the cell-surface receptor CD229 (Ly9, a SLAM family receptor) (www.aging-us.com) (www.aging-us.com). Intriguingly, CD229 binding to RASAL3 was associated with enhanced Ras/ERK activation and increased myeloma cell proliferation (www.aging-us.com) (www.aging-us.com). One interpretation is that upon CD229 activation (via its ITSM motifs being phosphorylated), the receptor sequesters or inactivates RASAL3, thereby relieving Ras from negative regulation and boosting ERK signaling (www.aging-us.com) (www.aging-us.com). This example illustrates how RASAL3 might be integrated into signaling networks: it can be a node where extracellular receptor signals modulate the Ras pathway by regulating GAP activity. While the CD229–RASAL3 interaction requires further mechanistic study, it underscores that RASAL3’s role is not isolated – it can be influenced by and contribute to larger signaling modules (in this case, influencing oncogenic signaling in a B-cell malignancy).

Clinical and Therapeutic Relevance

Given its role as a Ras pathway suppressor in immune cells and other contexts, RASAL3 has attracted interest for its potential involvement in diseases:

• Autoimmunity and Inflammation: By dampening neutrophil activation, RASAL3 could be a protective factor against hyperinflammatory conditions such as sepsis. The 2021 study suggested that boosting RASAL3 function might be a strategy to mitigate septic shock or severe inflammatory responses (pmc.ncbi.nlm.nih.gov). Conversely, individuals with low RASAL3 activity might be prone to exaggerated inflammation. While there are no known human mutations in RASAL3 linked to immunological disorders yet, its role in animal models positions RASAL3 as a possible therapeutic target for inflammatory diseases – for example, drugs that enhance RASAL3 activity in neutrophils could help turn down excessive inflammation (pmc.ncbi.nlm.nih.gov).

• Cancer: Dysregulation of RASAL3 can influence cancer-related processes, especially in contexts where the tumor microenvironment or immune cells are involved. RASAL3 itself is not a commonly mutated gene in cancers, but its expression can be altered epigenetically. A notable example comes from prostate cancer stroma: In aggressive prostate tumors, carcinoma-associated fibroblasts (CAFs) were found to epigenetically silence the RASAL3 gene as an adaptive response to therapy. This loss of RASAL3 in the stroma leads to hyperactive Ras signaling in CAFs, which in turn drives macropinocytosis and glutamine synthesis to feed the tumor cells (pmc.ncbi.nlm.nih.gov). In a 2018 study (J. Clin. Invest.), Mishra et al. showed that androgen-deprivation therapy (ADT) in prostate cancer can trigger EZH2-mediated epigenetic silencing of RASAL3 in stromal fibroblasts (pmc.ncbi.nlm.nih.gov). The reduced RASAL3 levels allow sustained Ras activity in those fibroblasts, thereby increasing the secretion of glutamine and other nutrients that help prostate cancer cells survive and develop therapy resistance (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In other words, loss of RASAL3 in the tumor microenvironment “fuels” cancer growth under treatment stress. This finding identifies RASAL3 as a stromal tumor suppressor: keeping RASAL3 active in CAFs constrains tumor-supportive metabolic reprogramming, whereas losing it promotes tumor progression (pmc.ncbi.nlm.nih.gov). There are even suggestions of targeting this mechanism – e.g. using EZH2 inhibitors to prevent RASAL3 silencing – as a therapeutic angle to counteract resistance in prostate cancer (pmc.ncbi.nlm.nih.gov).

• Hematological malignancies: As mentioned, RASAL3 might have a role in diseases like multiple myeloma, where it interacts with signaling receptors (CD229) on malignant plasma cells (www.aging-us.com) (www.aging-us.com). The exact outcome of RASAL3’s function in that context appears to paradoxically assist Ras/ERK activation (potentially by a sequestration mechanism), thus contributing to myeloma cell proliferation (www.aging-us.com). It points to a complex role where cancer cells might hijack a RasGAP to fine-tune signaling to their advantage. Further research is needed, but RASAL3 or its interactors could become targets in certain leukemias or lymphomas, especially if those cancers rely on Ras signaling moderated by immune cell interactions.

Overall, RASAL3’s significance is twofold: biologically, it is a crucial negative regulator of Ras signals in immune cells, ensuring balanced cell survival and activation; clinically, its dysregulation can contribute to pathological states (ranging from uncontrolled inflammation to tumor progression), making it a potential biomarker or target. Experts in immunology and oncology view RASAL3 as part of the wider network of Ras regulators that maintain cellular homeostasis (pmc.ncbi.nlm.nih.gov). Its discovery as “the most recently identified RasGAP” (www.aging-us.com) has filled a gap in our understanding of how immune cells keep Ras in check. In the words of one review, RasGAPs like RASAL3 act as “off switches” for Ras, and losing these switches leads to aberrant Ras activity driving disease (pmc.ncbi.nlm.nih.gov). With continued research, there is optimism that manipulating RASAL3 or its pathway could provide new strategies to modulate immune responses or combat Ras-driven aspects of diseases.

References: RASAL3 functional insights have been drawn from curated database annotations (www.ncbi.nlm.nih.gov) and in vitro as well as in vivo studies. Key experimental evidence includes Muro et al. 2015 (PLOS ONE) for T cell function (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), Sakamoto et al. 2015 (Eur. J. Immunol.) for NKT cells (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov), Shin et al. 2018 (Biomed. Reports) for Rac2 GAP activity (pmc.ncbi.nlm.nih.gov), and Saito et al. 2021 (Front. Immunol.) for neutrophil inflammation and sepsis models (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Additionally, the role of RASAL3 in prostate cancer stroma was described by Mishra et al. 2018 (JCI) (pmc.ncbi.nlm.nih.gov), and the CD229-RASAL3 interaction in myeloma by Lin et al. 2022 (Aging) (www.aging-us.com) (www.aging-us.com). These studies collectively establish our current understanding of RASAL3’s function, localization, and importance in cellular signaling. Each new finding underscores the theme that RASAL3 serves as a critical attenuator of Ras signaling, with diverse consequences for cell physiology and disease when that attenuation is lost.

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46. AnnotationURLCitation(end_index=15300, start_index=15138, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=phosphorylation%20in%20a%20T%20cell,contributing%20to%20the%20maintenance%20of')
47. AnnotationURLCitation(end_index=15628, start_index=15504, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=%CE%B2,of%20optimal%20T%20cell%20numbers')
48. AnnotationURLCitation(end_index=15802, start_index=15629, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=adoptive%20transfer%20was%20significantly%20impaired%2C,of%20optimal%20T%20cell%20numbers')
49. AnnotationURLCitation(end_index=16163, start_index=16018, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=physiological%20roles%20of%20Rasal3,dependent%20survival%20of')
50. AnnotationURLCitation(end_index=16326, start_index=16164, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=phosphorylation%20in%20a%20T%20cell,contributing%20to%20the%20maintenance%20of')
51. AnnotationURLCitation(end_index=16671, start_index=16509, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=phosphorylation%20in%20a%20T%20cell,contributing%20to%20the%20maintenance%20of')
52. AnnotationURLCitation(end_index=16965, start_index=16841, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=%CE%B2,of%20optimal%20T%20cell%20numbers')
53. AnnotationURLCitation(end_index=17369, start_index=17239, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=development%20of%20various%20types%20of,GalCer%20in')
54. AnnotationURLCitation(end_index=17655, start_index=17498, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=cells%20of%20hematopoietic%20lineages%2C%20including,deficient%20mice.%20Taken')
55. AnnotationURLCitation(end_index=17991, start_index=17862, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=systemic%20RASAL3,an%20important%20role%20in%20the')
56. AnnotationURLCitation(end_index=18326, start_index=18197, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=systemic%20RASAL3,an%20important%20role%20in%20the')
57. AnnotationURLCitation(end_index=18536, start_index=18433, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=with%20%CE%B1,associated')
58. AnnotationURLCitation(end_index=18901, start_index=18744, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=vitro%20presented%20augmented%20Erk%20phosphorylation%2C,associated%20diseases')
59. AnnotationURLCitation(end_index=19290, start_index=19133, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=vitro%20presented%20augmented%20Erk%20phosphorylation%2C,associated%20diseases')
60. AnnotationURLCitation(end_index=19631, start_index=19474, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=vitro%20presented%20augmented%20Erk%20phosphorylation%2C,associated%20diseases')
61. AnnotationURLCitation(end_index=19824, start_index=19694, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=development%20of%20various%20types%20of,GalCer%20in')
62. AnnotationURLCitation(end_index=20396, start_index=20254, title='RASAL3 RAS protein activator like 3 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/64926#:~:text=Expression%20Broad%20expression%20in%20lymph,Try%20the%20new%20%2015')
63. AnnotationURLCitation(end_index=21211, start_index=21075, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=understood,mortality%20were%20recapitulated%20in%20a')
64. AnnotationURLCitation(end_index=21369, start_index=21212, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=Here%2C%20we%20show%20that%20RASAL3%2C,functions%20as%20a%20RasGAP%20that')
65. AnnotationURLCitation(end_index=21735, start_index=21599, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=understood,mortality%20were%20recapitulated%20in%20a')
66. AnnotationURLCitation(end_index=21901, start_index=21736, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=RASAL3%20is%20dominantly%20expressed%20in,expression%20level%20of%20RASAL3%20mRNA')
67. AnnotationURLCitation(end_index=22242, start_index=22108, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=NF,KO%20neutrophils%20%28Figures%C2%A02D%E2%80%93F')
68. AnnotationURLCitation(end_index=22355, start_index=22243, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=upregulated%20in%20RASAL3,KO')
69. AnnotationURLCitation(end_index=22677, start_index=22520, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=Here%2C%20we%20show%20that%20RASAL3%2C,functions%20as%20a%20RasGAP%20that')
70. AnnotationURLCitation(end_index=22841, start_index=22678, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=were%20followed%20for%2072%20h%2C,RASAL3%20is%20associated%20with%20unregulated')
71. AnnotationURLCitation(end_index=23216, start_index=23053, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=were%20followed%20for%2072%20h%2C,RASAL3%20is%20associated%20with%20unregulated')
72. AnnotationURLCitation(end_index=23524, start_index=23367, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=Here%2C%20we%20show%20that%20RASAL3%2C,functions%20as%20a%20RasGAP%20that')
73. AnnotationURLCitation(end_index=23656, start_index=23525, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=%28RASAL3,to%20have%20low%20neutrophil%20RASAL3')
74. AnnotationURLCitation(end_index=24004, start_index=23830, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=deficiency%20triggers%20augmented%20neutrophil%20responses,RASAL3%20could%20serve%20as%20a')
75. AnnotationURLCitation(end_index=24388, start_index=24231, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=Here%2C%20we%20show%20that%20RASAL3%2C,functions%20as%20a%20RasGAP%20that')
76. AnnotationURLCitation(end_index=24527, start_index=24389, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=%28RASAL3,and%20many%20inflammatory%20disease%20states')
77. AnnotationURLCitation(end_index=24867, start_index=24733, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=NF,KO%20neutrophils%20%28Figures%C2%A02D%E2%80%93F')
78. AnnotationURLCitation(end_index=25976, start_index=25842, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=NF,KO%20neutrophils%20%28Figures%C2%A02D%E2%80%93F')
79. AnnotationURLCitation(end_index=26325, start_index=26176, title='RASAL3 preferentially stimulates GTP hydrolysis of the Rho family small GTPase Rac2 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6158391/#:~:text=Although%20RASAL3%20has%20been%20identified,Rac2%20was%20detected')
80. AnnotationURLCitation(end_index=26721, start_index=26567, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=CD229%20interacts%20with%20RASAL3%20protein,the%20RAS%2FERK%20pathway%20in%20MM')
81. AnnotationURLCitation(end_index=26877, start_index=26722, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=match%20at%20L245%20cells%20confirmed,the%20RAS%2FERK%20signaling%20pathway%20by')
82. AnnotationURLCitation(end_index=27173, start_index=27008, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=signaling%20pathway%20via%20interacting%20with,therapeutic%20target%20for%20MM%20treatment')
83. AnnotationURLCitation(end_index=27323, start_index=27174, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=match%20at%20L360%20between%20CD229,currently%20a%20clinical%20agent%20for')
84. AnnotationURLCitation(end_index=27692, start_index=27543, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=match%20at%20L360%20between%20CD229,currently%20a%20clinical%20agent%20for')
85. AnnotationURLCitation(end_index=27837, start_index=27693, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=between%20CD229%20and%20RASAL3,currently%20a%20clinical%20agent%20for')
86. AnnotationURLCitation(end_index=28918, start_index=28780, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=%28RASAL3,and%20many%20inflammatory%20disease%20states')
87. AnnotationURLCitation(end_index=29458, start_index=29320, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=%28RASAL3,and%20many%20inflammatory%20disease%20states')
88. AnnotationURLCitation(end_index=30256, start_index=30120, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=cell%20cycle%20arrest%20through%20the,ADT%20further')
89. AnnotationURLCitation(end_index=30584, start_index=30456, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=match%20at%20L289%20induces%20epigenetic,56')
90. AnnotationURLCitation(end_index=30936, start_index=30800, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=cell%20cycle%20arrest%20through%20the,ADT%20further')
91. AnnotationURLCitation(end_index=31074, start_index=30937, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=induces%20epigenetic%20silencing%20of%20RASAL3%2C,56')
92. AnnotationURLCitation(end_index=31502, start_index=31377, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=RASAL3%20%20,and%20glutamine%20secretion')
93. AnnotationURLCitation(end_index=31859, start_index=31689, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=match%20at%20L747%20tumor%20heterogeneity,using%20EZH2%20inhibitors%20to%20reactivate')
94. AnnotationURLCitation(end_index=32203, start_index=32049, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=CD229%20interacts%20with%20RASAL3%20protein,the%20RAS%2FERK%20pathway%20in%20MM')
95. AnnotationURLCitation(end_index=32353, start_index=32204, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=match%20at%20L360%20between%20CD229,currently%20a%20clinical%20agent%20for')
96. AnnotationURLCitation(end_index=32712, start_index=32553, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=match%20at%20L350%20activates%20RAS%2FERK,pathway%20by%20interacting%20with%20RASAL3')
97. AnnotationURLCitation(end_index=33677, start_index=33513, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=Furthermore%2C%20research%20has%20also%20revealed,independent%20pathways%20%5B7')
98. AnnotationURLCitation(end_index=33894, start_index=33734, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=regulatory%20role%20in%20cellular%20proliferation,GDP%2C%20thereby%20functioning%20as')
99. AnnotationURLCitation(end_index=34299, start_index=34128, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=The%20RAS%20signaling%20pathway%2C%20a,overactive%2C%20fueling%20cancer%20growth%20and')
100. AnnotationURLCitation(end_index=34733, start_index=34579, title='RASAL3 RAS protein activator like 3 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/64926#:~:text=This%20gene%20belongs%20to%20the,results%20in%20multiple%20transcript%20variants')
101. AnnotationURLCitation(end_index=35009, start_index=34864, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=physiological%20roles%20of%20Rasal3,dependent%20survival%20of')
102. AnnotationURLCitation(end_index=35172, start_index=35010, title='The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4368693/#:~:text=phosphorylation%20in%20a%20T%20cell,contributing%20to%20the%20maintenance%20of')
103. AnnotationURLCitation(end_index=35333, start_index=35230, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=with%20%CE%B1,associated')
104. AnnotationURLCitation(end_index=35491, start_index=35334, title='RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25652366/#:~:text=vitro%20presented%20augmented%20Erk%20phosphorylation%2C,associated%20diseases')
105. AnnotationURLCitation(end_index=35701, start_index=35552, title='RASAL3 preferentially stimulates GTP hydrolysis of the Rho family small GTPase Rac2 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6158391/#:~:text=Although%20RASAL3%20has%20been%20identified,Rac2%20was%20detected')
106. AnnotationURLCitation(end_index=35948, start_index=35791, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=Here%2C%20we%20show%20that%20RASAL3%2C,functions%20as%20a%20RasGAP%20that')
107. AnnotationURLCitation(end_index=36112, start_index=35949, title='RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8579101/#:~:text=were%20followed%20for%2072%20h%2C,RASAL3%20is%20associated%20with%20unregulated')
108. AnnotationURLCitation(end_index=36353, start_index=36217, title='A Systematic Analysis of Expression and Function of RAS GTPase-Activating Proteins (RASGAPs) in Urological Cancers: A Mini-Review - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12071082/#:~:text=cell%20cycle%20arrest%20through%20the,ADT%20further')
109. AnnotationURLCitation(end_index=36582, start_index=36428, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=CD229%20interacts%20with%20RASAL3%20protein,the%20RAS%2FERK%20pathway%20in%20MM')
110. AnnotationURLCitation(end_index=36732, start_index=36583, title='CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation | Aging', type='url_citation', url='https://www.aging-us.com/article/204405/text#:~:text=match%20at%20L360%20between%20CD229,currently%20a%20clinical%20agent%20for')