Affinage

RASAL3

RAS protein activator like-3 · UniProt Q86YV0

Length
1011 aa
Mass
111.9 kDa
Annotated
2026-04-28
23 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASAL3 is a hematopoietic RasGAP that negatively regulates Ras/ERK signaling to control immune cell survival, activation, and migration. RASAL3 possesses RasGAP activity (but not Rap1GAP activity) and additionally stimulates Rac2 GTPase activity in vitro; in T cells and NKT cells, it represses TCR-stimulated ERK phosphorylation, and its genetic ablation causes increased apoptosis of naive and activated T cells (with reduced Bcl2 expression), depletion of NKT cells, and neutrophil hyperinflammation (PMID:25793935, PMID:25652366, PMID:29291408, PMID:34777356). Optogenetic studies in neutrophils and macrophages demonstrate that local RASAL3-mediated Ras suppression extinguishes protrusions and redirects migration, while global Ras suppression drives myosin II–dependent rear contractility and mTORC2-dependent front actin polymerization, producing cell polarization and accelerated movement (PMID:37220748, PMID:38951708). RASAL3 forms a complex with CCDC88B and ARHGEF2 that opposes RHOA activation to regulate dendritic cell migration, and epigenetic silencing of RASAL3 in cancer-associated fibroblasts activates Ras-driven macropinocytosis and glutamine secretion that fuels prostate cancer progression (PMID:38200184, PMID:30047926).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2015 High

    Establishing that RASAL3 is a bona fide RasGAP required for T and NKT cell homeostasis resolved the identity of the RasGAP governing Ras/ERK signaling downstream of TCR engagement in lymphocytes.

    Evidence In vitro RasGAP/Rap1GAP assays, ERK phosphorylation in T cell lines, systemic RASAL3-KO mice with flow cytometry and adoptive transfer; parallel KO analysis of NKT cells with α-GalCer stimulation and cytokine measurement

    PMID:25652366 PMID:25793935

    Open questions at the time
    • Structural basis for Ras selectivity over Rap1 unknown
    • Mechanism linking excess ERK activity to apoptosis rather than proliferation in naive T cells not defined
  2. 2017 Medium

    Demonstrating that RASAL3-deficient activated T cells die with reduced Bcl2 in a contact hypersensitivity model established that RASAL3 controls inflammatory magnitude by supporting survival of both naive and effector T cells.

    Evidence RASAL3-KO mice in Th1/Th2 contact hypersensitivity models with Bcl2 expression analysis

    PMID:29291408

    Open questions at the time
    • Whether RASAL3 directly regulates Bcl2 transcription or acts indirectly through ERK not resolved
    • Single-lab observation without independent replication
  3. 2018 High

    Showing that RASAL3 epigenetic silencing in cancer-associated fibroblasts activates Ras-driven macropinocytosis and glutamine secretion that fuels prostate cancer revealed a tumor-extrinsic, stromal function for RASAL3 loss beyond immune cells.

    Evidence CAF epigenetic profiling, orthotopic xenograft models, macropinocytosis and glutamine transport inhibition, clinical sample validation

    PMID:30047926

    Open questions at the time
    • Whether RASAL3 silencing occurs in fibroblasts of other tumor types not explored
    • Direct link between specific Ras isoform activation and macropinocytosis induction not defined
  4. 2018 Medium

    Discovering that the RASAL3 catalytic domain stimulates Rac2 GTPase activity in vitro expanded RASAL3's substrate repertoire beyond Ras to the hematopoietic Rho-family GTPase Rac2.

    Evidence In vitro GTPase activity assay with purified RASAL3 GAP domain and Rac2

    PMID:30271600

    Open questions at the time
    • Rac2GAP activity not confirmed in cellular context
    • Structural basis for dual Ras/Rac2 specificity not characterized
    • Single-method, single-lab result
  5. 2021 High

    Extending RASAL3's immune role to neutrophils, where its loss triggers hyperinflammation and accelerated septic mortality, showed that RASAL3 is a broad negative regulator across innate and adaptive immune lineages.

    Evidence RASAL3-KO mice in LPS septic shock and sickle cell disease models, neutrophil activation assays

    PMID:34777356

    Open questions at the time
    • Specific Ras isoform(s) hyperactivated in neutrophils not identified
    • Whether Rac2GAP activity contributes to neutrophil phenotype untested
  6. 2022 Medium

    Identification of CD229 (SLAMF3) as a RASAL3-interacting partner in myeloma cells suggested a receptor-proximal mechanism by which RASAL3 is recruited to regulate Ras/ERK at the plasma membrane.

    Evidence Co-immunoprecipitation coupled with mass spectrometry, co-culture immunofluorescence, proliferation assays, xenograft model

    PMID:36445333

    Open questions at the time
    • Reciprocal Co-IP not described
    • Whether SLAMF3-RASAL3 interaction is direct or scaffolded not resolved
    • Unclear if this interaction is generalizable beyond myeloma
  7. 2023 High

    Optogenetic studies revealed that RASAL3-mediated local Ras suppression directly controls protrusion and migration direction, while global Ras suppression paradoxically drives mTORC2-dependent polarization, uncovering a spatial logic for RasGAP function in cell motility.

    Evidence Light-inducible membrane recruitment of RASAL3 in HL-60 neutrophils and RAW 264.7 macrophages, live-cell imaging, PI3K and mTORC2 pharmacological inhibition

    PMID:37220748

    Open questions at the time
    • Molecular link from global Ras suppression to mTORC2 activation unclear
    • Role of Rac2GAP activity versus RasGAP activity in migration phenotype not dissected
  8. 2023 Medium

    Demonstrating that ALKBH5-dependent m6A demethylation stabilizes Rasal3 mRNA revealed an epitranscriptomic layer of RASAL3 regulation, linking its expression to cardiomyocyte survival under doxorubicin stress.

    Evidence Alkbh5-KO, knock-in, and cardiac-specific KO mice; m6A modification analysis; RAS/RAF/ERK signaling and apoptosis readouts

    PMID:36876119

    Open questions at the time
    • Whether m6A regulation of RASAL3 operates in hematopoietic cells unknown
    • Specific m6A sites on Rasal3 mRNA not mapped
    • Single-lab observation
  9. 2024 High

    Identification of a CCDC88B/RASAL3/ARHGEF2 complex that oppositely regulates RHOA in dendritic cells established a multiprotein signaling module through which RASAL3 restrains DC migration and neuroinflammation.

    Evidence Reciprocal Co-IP, proximity-ligation assay, Rasal3-mutant DC migration assays, RHOA activation assays, EAE and colitis mouse models

    PMID:38200184

    Open questions at the time
    • How RASAL3's RasGAP activity integrates with RHOA regulation through ARHGEF2 is mechanistically unresolved
    • Stoichiometry and structure of the ternary complex unknown
  10. 2024 High

    A refined optogenetic and computational analysis established that RASAL3-induced polarization depends on myosin II–mediated rear contractility preceding sustained mTORC2-driven front protrusion, defining the temporal sequence of the RasGAP-driven polarization circuit.

    Evidence Optogenetic rear-targeted and global RASAL3 recruitment in HL-60 and RAW cells, myosin II and mTORC2 inhibition, computational simulation

    PMID:38951708

    Open questions at the time
    • Identity of the upstream sensor that couples Ras suppression to myosin II activation unknown
    • Whether this polarization circuit operates in vivo during chemotaxis not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RASAL3's dual RasGAP and Rac2GAP activities are coordinated in vivo, and whether the CCDC88B/RASAL3/ARHGEF2 complex operates in cell types beyond dendritic cells, remain open questions.
  • No structural model of RASAL3 exists
  • Relative contribution of RasGAP vs Rac2GAP activity to each physiological phenotype not dissected
  • Whether myosin II–mTORC2 polarization axis downstream of RASAL3 functions during in vivo immune surveillance untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 2
Partners
ALKBH5ARHGEF2CCDC88BRAC2SLAMF3
Complex memberships
CCDC88B/RASAL3/ARHGEF2 complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 RASAL3 possesses RasGAP activity (but not Rap1GAP activity) and represses TCR-stimulated ERK phosphorylation in T cells; systemic RASAL3-deficient mice show reduced peripheral naive CD4 and CD8 T cells due to increased apoptosis, establishing RASAL3 as required for naive T cell survival in vivo. In vitro RasGAP/Rap1GAP activity assays, ERK phosphorylation assays in T cell lines, systemic knockout mice with flow cytometry and adoptive transfer experiments PloS one High 25793935
2015 RASAL3 is predominantly expressed in hematopoietic cells (NKT, B, T cells) and negatively regulates Ras/ERK signaling in NKT cells; RASAL3-deficient mice show severe decrease of NKT cells in liver and reduced IL-4/IFN-γ production, with augmented ERK phosphorylation in RASAL3-deficient NKT cells upon α-GalCer stimulation. Systemic RASAL3-knockout mice, α-GalCer stimulation, flow cytometry, ERK phosphorylation assays, cytokine measurement European journal of immunology High 25652366
2017 Rasal3-deficient mice show ameliorated Th1- and Th2-dependent contact hypersensitivity reactions due to increased death of activated T cells with reduced Bcl2 expression, demonstrating that Rasal3 controls inflammatory response magnitude by supporting survival of both naive and activated T cells. Rasal3-knockout mice, contact hypersensitivity model, flow cytometry, Bcl2 expression analysis Biochemical and biophysical research communications Medium 29291408
2018 RASAL3 is epigenetically silenced (promoter hypermethylation) in cancer-associated fibroblasts (CAF), leading to oncogenic Ras activity that drives macropinocytosis-mediated glutamine synthesis; stromal glutamine fuels prostate cancer anaplerosis and neuroendocrine differentiation. Epigenetic analysis of CAF, orthotopic xenograft models, macropinocytosis inhibition, glutamine transport inhibition, androgen deprivation therapy models The Journal of clinical investigation High 30047926
2018 The catalytic (GAP) domain of RASAL3 interacts with Rac2 and stimulates Rac2 GTPase activity in vitro, whereas p50 rhoGAP did not markedly affect Rac2 activity, indicating RASAL3 has RasGAP family activity toward the hematopoietic Rho GTPase Rac2. In vitro GTPase activity assay with purified RASAL3 catalytic domain and Rac2 Biomedical reports Medium 30271600
2021 RASAL3 is highly expressed in neutrophils, its expression is upregulated by exogenous stimuli, and RASAL3 deficiency triggers augmented neutrophil responses and hyperinflammation; RASAL3-KO mice show accelerated mortality in a septic shock model via severe organ damage and hyperinflammatory neutrophil response. RASAL3-knockout mice, LPS septic shock model, sickle cell disease mouse model, neutrophil activation assays Frontiers in immunology High 34777356
2022 CD229 (SLAMF3) interacts with RASAL3 as identified by co-immunoprecipitation coupled with mass spectrometry; intercellular tyrosine phosphorylation-mediated self-activation of CD229 activates the RAS/ERK signaling pathway via interaction with RASAL3 to promote multiple myeloma cell proliferation. Co-immunoprecipitation coupled with mass spectrometry, co-culture with immunofluorescence assay, in vitro proliferation assays, xenograft mouse model Aging Medium 36445333
2023 Optogenetic recruitment of RASAL3 to the cell front of HL-60 neutrophils extinguished protrusions and changed migration direction; global membrane recruitment caused cells to polarize and move more rapidly in an mTORC2-dependent but largely PI3K-independent manner, establishing RASAL3 as a direct regulator of actin assembly, cell polarity, and migration via Ras suppression. Optogenetic targeting (light-inducible recruitment) in differentiated HL-60 neutrophils and RAW 264.7 macrophages, live-cell imaging, pharmacological inhibition of mTORC2 and PI3K Developmental cell High 37220748
2023 ALKBH5 (m6A demethylase) regulates Rasal3 mRNA stability in an m6A-dependent posttranscriptional manner; ALKBH5 deficiency reduces Rasal3 expression, thereby activating RAS/RAF/ERK signaling and increasing cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity. Alkbh5-knockout, knockin, and myocardial-specific knockout mice; cardiac function assessment; m6A modification analysis; signal transduction studies iScience Medium 36876119
2024 RASAL3 physically and functionally interacts with CCDC88B and ARHGEF2 as part of a complex; Rasal3-mutant dendritic cells show enhanced migratory properties in vitro, and RASAL3 and ARHGEF2 act in opposing fashions to regulate RHOA activation, establishing a CCDC88B/RASAL3/ARHGEF2 complex that controls DC migration. Co-immunoprecipitation, proximity-ligation assay, Rasal3-mutant mouse DC migration assays, RHOA activation assays, neuroinflammation and colitis mouse models Communications biology High 38200184
2024 Optogenetic global or rear-targeted recruitment of RASAL3 in HL-60 neutrophils and macrophages causes cell polarization and accelerated migration through increased rear actomyosin contractility followed by sustained mTORC2-dependent actin polymerization at the front; this RasGAP-mediated polarization depends critically on myosin II activity. Optogenetic membrane recruitment in HL-60 neutrophils and RAW 264.7 macrophages, live-cell imaging, myosin II inhibition, mTORC2 inhibition, computational simulations Nature cell biology High 38951708

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. The Journal of clinical investigation 140 30047926
2019 Epigenetic changes in fibroblasts drive cancer metabolism and differentiation. Endocrine-related cancer 37 31627186
2018 Transcriptome Analysis of Bronchoalveolar Lavage Fluid From Children With Mycoplasma pneumoniae Pneumonia Reveals Natural Killer and T Cell-Proliferation Responses. Frontiers in immunology 35 29967623
2015 RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells. European journal of immunology 32 25652366
2023 Actuation of single downstream nodes in growth factor network steers immune cell migration. Developmental cell 29 37220748
2015 The Ras GTPase-activating protein Rasal3 supports survival of naive T cells. PloS one 21 25793935
2017 RNA-seq implicates deregulation of the immune system in the pathogenesis of diverticulitis. American journal of physiology. Gastrointestinal and liver physiology 19 28619727
2015 Identification of potential mutations and genomic alterations in the epithelial and spindle cell components of biphasic synovial sarcomas using a human exome SNP chip. BMC medical genomics 19 26503545
2021 Differential DNA Methylation Profiles in Patients with Temporal Lobe Epilepsy and Hippocampal Sclerosis ILAE Type I. Journal of molecular neuroscience : MN 18 33403589
2020 Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model? European journal of human genetics : EJHG 17 32514133
2021 RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils. Frontiers in immunology 16 34777356
2024 Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration. Nature cell biology 15 38951708
2021 Transcriptomics unravels molecular players shaping dorsal lip hypertrophy in the vacuum cleaner cichlid, Gnathochromis permaxillaris. BMC genomics 13 34225643
2017 Rasal3-mediated T cell survival is essential for inflammatory responses. Biochemical and biophysical research communications 13 29291408
2023 m6A demethylase ALKBH5 attenuates doxorubicin-induced cardiotoxicity via posttranscriptional stabilization of Rasal3. iScience 8 36876119
2020 The impact of blood-processing time on the proteome of human peripheral blood mononuclear cells. Biochimica et biophysica acta. Proteins and proteomics 8 33301959
2021 DNA Methylome Mapping Identifies Epigenetic Abnormalities in Intestinal Lymphocyte Regulation in Human Necrotizing Enterocolitis. Digestive diseases and sciences 6 34846677
2024 CCDC88B interacts with RASAL3 and ARHGEF2 and regulates dendritic cell function in neuroinflammation and colitis. Communications biology 5 38200184
2021 [Expression of RASGRP2 in Lung Adenocarcinoma and Its Effect 
on Immune Microenvironment]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 5 34157800
2022 CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation. Aging 4 36445333
2019 Change of Ras and its guanosine triphosphatases (GTPases) during development and regression in bovine corpus luteum. Theriogenology 3 31887652
2023 Ras-mediated homeostatic control of front-back signaling dictates cell polarity. bioRxiv : the preprint server for biology 1 37693515
2018 RASAL3 preferentially stimulates GTP hydrolysis of the Rho family small GTPase Rac2. Biomedical reports 1 30271600