| 2015 |
RASAL3 possesses RasGAP activity but not Rap1GAP activity, and represses TCR-stimulated ERK phosphorylation in T cells. In systemic Rasal3-deficient mice, naive CD4 and CD8 T cells in the periphery were significantly reduced due to increased apoptosis, while thymic T cell development (positive, negative, and β-selection) was unaffected. In vivo adoptive transfer showed impaired survival of Rasal3-deficient naive CD4 T cells, whereas IL-7-dependent survival in vitro was unaltered. |
In vitro RasGAP/Rap1GAP activity assays, systemic Rasal3-knockout mice, flow cytometry, adoptive transfer, apoptosis assays |
PloS one |
High |
25793935
|
| 2015 |
RASAL3 is predominantly expressed in hematopoietic lineages (NKT, B, and T cells) and negatively regulates Ras/ERK signaling in NKT cells. RASAL3-deficient mice showed severe decrease in NKT cells in the liver, and RASAL3-deficient NKT cells treated with α-GalCer exhibited augmented ERK phosphorylation, confirming dysregulated Ras signaling. Loss of RASAL3 attenuated α-GalCer-induced liver damage and reduced IL-4 and IFN-γ production from NKT cells. |
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 and a shortage of T cells at regional lymph nodes. Activated Rasal3-deficient T cells showed increased cell death with reduced Bcl2 expression, indicating that Rasal3 is required for survival of both naive and activated T cells to control the magnitude of inflammatory responses. |
Systemic Rasal3-knockout mice, contact hypersensitivity models, flow cytometry, Bcl2 expression analysis, in vivo T cell transfer |
Biochemical and biophysical research communications |
Medium |
29291408
|
| 2018 |
RASAL3 is epigenetically silenced (promoter hypermethylation) in prostatic cancer-associated fibroblasts (CAF), leading to oncogenic Ras activation. This Ras activity drives macropinocytosis-mediated glutamine synthesis in CAF, providing glutamine to prostate cancer epithelial cells to fuel proliferation and promote neuroendocrine differentiation. ADT further promotes RASAL3 epigenetic silencing and glutamine secretion. |
Orthotopic xenograft models, macropinocytosis inhibition, glutamine transport inhibition, epigenetic analysis (methylation), castration-resistant xenograft rescue experiments |
The Journal of clinical investigation |
Medium |
30047926
|
| 2018 |
The catalytic (GAP) domain of RASAL3 interacts with and stimulates GTP hydrolysis of the Rho family GTPase Rac2 in vitro, in addition to its known activity on p21ras. By contrast, p50 rhoGAP did not markedly affect Rac2 GTPase activity but did accelerate activity of Rac1, RhoA, and Cdc42. |
In vitro GTPase activity assay with recombinant RASAL3 catalytic domain and Rac2 |
Biomedical reports |
Medium |
30271600
|
| 2021 |
RASAL3 is highly expressed in neutrophils and its expression is upregulated by exogenous inflammatory stimuli. RASAL3 deficiency (KO mice) triggers augmented neutrophil responses and hyperinflammation in acute inflammatory conditions, leading to accelerated mortality in a septic shock model via severe organ damage. Mice modeling sickle cell disease were found to have low neutrophil RASAL3 expression upon LPS activation, and this correlated with excessive neutrophilic hyperinflammation and increased mortality. |
RASAL3-KO mice, septic shock model, sickle cell disease mouse model, LPS stimulation, neutrophil functional assays, histology |
Frontiers in immunology |
Medium |
34777356
|
| 2023 |
Optogenetic recruitment of RASAL3 to the cell front of differentiated HL-60 neutrophils or RAW 264.7 macrophages extinguished protrusions and reversed migration direction. Global or rear-targeted RASAL3 recruitment caused cells to polarize and move more rapidly, effects that were mTORC2-dependent but relatively independent of PI3K. These findings demonstrate that local Ras suppression by RASAL3 directly controls actin assembly, cell shape, and migration mode in immune cells. |
Optogenetics (iLID/SspB system), HL-60 neutrophils and RAW 264.7 macrophages, live-cell imaging, pharmacological inhibition of mTORC2 and PI3K |
Developmental cell |
High |
37220748
|
| 2024 |
Optogenetic recruitment of RASAL3 to the front of HL-60 neutrophils or macrophages extinguished protrusions and changed migration direction. Uniform or rear-targeted RASAL3 recruitment paradoxically increased cell polarization and migration speed through myosin II-dependent rear contraction followed by mTORC2-dependent actin polymerization at the front. RASAL3 thus controls a front/back feedback loop in which Ras suppression at the rear drives enhanced polarity and motility. |
Optogenetics, HL-60 neutrophils, RAW 264.7 macrophages, myosin II inhibition (blebbistatin), mTORC2 inhibition, computational modeling, live-cell imaging |
Nature cell biology |
High |
38951708
|
| 2024 |
RASAL3 physically interacts with CCDC88B and ARHGEF2 (a Rho/Rac GEF) as identified by co-immunoprecipitation. The CCDC88B/RASAL3/ARHGEF2 complex regulates dendritic cell migration by modulating RHOA activation, with ARHGEF2 and RASAL3 acting in opposing regulatory fashions. Rasal3-mutant mice show dampened neuroinflammation and altered susceptibility to colitis, and Rasal3-mutant DCs show enhanced migratory properties in vitro. |
Co-immunoprecipitation, Rasal3-mutant mice, DC migration assays, neuroinflammation and colitis disease models, RHOA activity assays |
Communications biology |
Medium |
38200184
|
| 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, immunofluorescence co-culture assay, xenograft mouse model, in vitro proliferation assays |
Aging |
Medium |
36445333
|
| 2023 |
ALKBH5 (m6A demethylase) regulates Rasal3 mRNA stability in an m6A-dependent manner through posttranscriptional regulation. ALKBH5-mediated reduction of Rasal3 mRNA stability activates RAS signaling and inhibits apoptosis through the RAS/RAF/ERK pathway, thereby alleviating doxorubicin-induced cardiotoxicity. Alkbh5 whole-body KO and myocardial-specific KO mice showed increased mortality and aggravated cardiac injury, while ALKBH5 overexpression was protective. |
Alkbh5-knockout, knockin, and myocardial-specific KO mice, m6A-sequencing, mRNA stability assays, cardiac function assessment, RAS/ERK signaling analysis |
iScience |
Medium |
36876119
|
| 2023 |
Optogenetic targeting of RASAL3 to the cell front of HL-60 neutrophils extinguished existing protrusions and changed migration direction. Global or rear-targeted RASAL3 caused rapid cell polarization and faster migration, mediated by increased actomyosin contractility at the back and sustained localized F-actin polymerization at the front, with effects captured by computational simulations of Ras-controlled front/back feedback loops. |
Optogenetics, HL-60 neutrophils, Dictyostelium (C2GAPB ortholog comparison), computational modeling, live-cell imaging |
bioRxivpreprint |
Medium |
37693515
|