Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
A novel human RasGAP-like gene that maps within the prostate cancer susceptibility locus at chromosome 1q25.
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RASAL2 was originally cloned and shown to complement yeast Ira2 RasGAP mutants
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The gene maps to chromosome 1q25
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The protein has striking homology to Ras-specific GTPase-activating proteins
A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.
Large-scale mapping of human protein-protein interactions by mass spectrometry.
Hepatitis C virus infection protein network.
A proteome-scale map of the human interactome network.
Architecture of the human interactome defines protein communities and disease networks.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
OpenCell: Endogenous tagging for the cartography of human cellular organization.
A central chaperone-like role for 14-3-3 proteins in human cells.
RAS GAPs stimulate RAS GTPase activity
Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.
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DAB2IP and RASAL2 are concomitantly suppressed in the most aggressive luminal B breast tumors and cooperatively drive metastasis via RAS and NF-kB pathways
"Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo"
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Combined RASAL2/DAB2IP loss dramatically enhances activation of K-Ras, H-Ras, ERK and AKT in a greater-than-additive manner
"While the suppression of each RasGAP activated K-Ras, H-Ras, ERK and AKT, the concomitant ablation of both RasGAPs dramatically enhanced the activation of all of these components, which overall appeared to be greater than an additive effect"
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Concomitant loss of RASAL2 and DAB2IP in luminal B tumors strongly stratifies relapse-free survival (log rank p=3.1e-08)
"Moreover, in the context of luminal B disease alone, low levels of both genes together were associated with a significant decrease in relapse-free survival (Fig. 2D, log rank p=3.1e-08)."
PRKAA/AMPKα phosphorylation switches the role of RASAL2 from a suppressor to an activator of autophagy.
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Under basal conditions RASAL2 attenuates AMPK phosphorylation by recruiting phosphatase PPM1B to suppress basal autophagy
"Here we showed that RASAL2 can attenuate PRKAA/AMPKα phosphorylation by recruiting phosphatase PPM1B/pp2cβ, thus inhibiting the initiation of basal autophagy under normal conditions."
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Glucose starvation triggers AMPK-mediated S351 phosphorylation of RASAL2, which then binds the VPS34-ATG14-BECN1 complex to activate autophagy
"glucose starvation could induce dissociation of PPM1B from RASAL2 and then RASAL2 at S351 be phosphorylated by PRKAA, followed by the binding of phosphorylated-RASAL2 with to PIK3C3/VPS34-ATG14-BECN1/ Beclin1 complex to increase PIK3C3 activity and autophagy."
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RASAL2 S351 phosphorylation functions as a molecular switch between autophagy suppression and activation; it correlates with poor outcome in breast cancer patients
"the phosphorylation status of RASAL2 S351 can function as a molecular switch to either suppress or promote AMPK-mediated autophagy."
Cutting the Brakes on Ras-Cytoplasmic GAPs as Targets of Inactivation in Cancer.
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RASAL2 belongs to the SynGAP RasGAP subfamily and functions as a tumor suppressor in lung, ovarian, breast, and bladder cancer, where low expression correlates with Ras-ERK activation and worst prognosis
"The SynGAP family includes SynGAP (synaptic Ras GTPase-Activating Protein 1), DAB2IP (Dab2 interacting protein), RASAL2 (Ras protein activator like 2), and RASAL3"
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RASAL2 can be phosphorylated at Ser237 within the PH domain; increased phospho-RASAL2 is detected in aggressive ER-negative breast cancer cells
"a recent study uncovered that RASAL2 can be phosphorylated on Serine 237 within the PH domain. The impact on Ras has not been analyzed, but increased phospho-RASAL2 was detected in aggressive ER (estrogen receptor) negative breast cancer cells"
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RASAL2 is a cargo for the importin IPO5 in colorectal cancer; IPO5 binds an N-terminal NLS and sequesters RASAL2 away from membranes, blocking its signaling-suppressor activity
"RASAL2 is a cargo for the importin IPO5 in colorectal cancer. IPO5 sequesters RASAL2 by binding an NLS located in the N-terminal region, and prevents RASAL2 function as a signaling pathway suppressor"
Pumping the brakes on RAS - negative regulators and death effectors of RAS.
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Loss of RasGAP function (including RASAL2) is a common mechanism for aberrant RAS pathway activation in cancers lacking activating RAS mutations
"aberrant upregulation of RAS activity often occurs in the absence of activating mutations in the RAS genes due to defects in RAS regulators. It is now clear that loss of function of Ras GTPase-activating proteins (RasGAPs) is common in tumors"
Deep research on RASAL2 function (perplexity)
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RASAL2 is a dual-specificity GAP for Ras and Rap GTPases
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Functions as tumor suppressor in ER+ breast cancers but oncogenic in TNBC
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Contains PH, C2, and GAP domains
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Regulated by phosphorylation at S237 and S351 by AMPK
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Involved in autophagy regulation
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Interacts with ARHGAP24 to activate RAC1 in TNBC
Deep research on RASAL2 function (falcon, Edison)
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RASAL2 (~1139 aa) is a PH-C2-RasGAP domain protein whose canonical biochemical role is to accelerate GTP hydrolysis on RAS, placing it upstream of ERK/MAPK and PI3K/AKT as a negative regulator
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RASAL2 cooperates non-redundantly with DAB2IP as a SynGAP-family RasGAP; co-loss is associated with aggressive ER+ breast cancer and poor outcome
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AMPK-mediated S351 phosphorylation of RASAL2 switches it from an autophagy suppressor (via PPM1B recruitment) to an autophagy activator (via VPS34-ATG14-BECN1 binding) under glucose starvation
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Inhibition of basal autophagy by RASAL2 is reported to be independent of RasGAP catalytic activity, although the GAP domain itself is required for this inhibitory role
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Additional candidate AMPK-related phosphosites on RASAL2 identified by LKB1-dependent phosphoproteomics include S56, S89, S736, S864, S899