RASAL2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005096 GTPase activator activity	IBA GO_REF:0000033	ACCEPT	Summary: RASAL2 is a well-characterized GTPase-activating protein (GAP) that stimulates GTP hydrolysis of Ras and Rap small GTPases. The IBA annotation is supported by phylogenetic analysis and is consistent with extensive literature evidence demonstrating that RASAL2 functions as a RasGAP. Expression in Saccharomyces cerevisiae defective in Ira2 (a yeast RasGAP) complemented loss of Ira2 function [PMID:9877179]. The GAP domain contains a conserved arginine residue (R369) that functions as an "arginine finger" essential for catalysis [Reactome:R-HSA-5658435, UniProt:Q9UJF2]. Reason: This is a core molecular function of RASAL2. The protein contains a well-characterized RasGAP domain and has demonstrated GAP activity both in genetic complementation assays and biochemical studies. The IBA annotation is appropriate and supported by extensive evidence. Supporting Evidence: PMID:9877179 Expression of the cDNA in Saccharomyces cerevisiae defective in one of two RasGAPs, Ira2, complemented loss of the Ira2 function, indicating that the cDNA product functions as a RasGAP. file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 functions biochemically as a GTPase-activating protein (GAP) that dramatically accelerates the hydrolysis of guanosine triphosphate (GTP) bound to small GTPases of the Ras family. PMID:33563064 RASAL2 (RAS protein activator like 2), a RASGTPase activating protein, can catalyze the hydrolysis of RAS-GTP into RAS-GDP to inactivate the RAS pathway in various types of cancer cells. file:human/RASAL2/RASAL2-deep-research-falcon.md Primary molecular function (RASAL2): by definition and domain composition, RASAL2's canonical biochemical role is to act as a RasGAP that down-regulates RAS signaling by accelerating GTP hydrolysis on RAS.
GO:1902531 regulation of intracellular signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: RASAL2 regulates intracellular signal transduction through its GAP activity on Ras proteins, which are central mediators of signal transduction cascades downstream of receptor tyrosine kinases. RASAL2 negatively regulates the RAS-MAPK pathway, and loss of RASAL2 results in elevated Ras-GTP levels and hyperactivation of downstream signaling including MAPK/ERK and PI3K/Akt pathways [file:human/RASAL2/RASAL2-deep-research-perplexity.md]. Reason: This annotation accurately captures the biological process role of RASAL2. By regulating Ras GTPase activity, RASAL2 directly modulates intracellular signal transduction pathways. The IBA annotation is appropriate and consistent with the documented role of RASAL2 in Ras-MAPK signaling regulation. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 functions as a negative regulator of the RAS-MAPK signaling pathway by catalyzing GTP hydrolysis of Ras proteins, thereby preventing accumulation of active Ras-GTP that drives proliferation, survival, and transformation signals. PMID:27974415 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 PMID:33096593 RASAL2 functions as a tumor suppressor in a broad range of human tumors, including lung, ovarian, breast, and bladder cancer; low RASAL2 expression often correlates with aberrant Ras-ERK activation and worst prognosis
GO:0005096 GTPase activator activity	IEA GO_REF:0000043	ACCEPT	Summary: This IEA annotation is based on UniProtKB/Swiss-Prot keyword mapping for "GTPase activation". While less specific than the IBA annotation, it is accurate and consistent with RASAL2's demonstrated GAP activity. Reason: This annotation correctly identifies the core molecular function of RASAL2. Although it duplicates the IBA annotation, IEA annotations based on keyword mapping are acceptable when they accurately reflect protein function. The annotation is appropriately broad for the evidence type. Supporting Evidence: PMID:9877179 We report the molecular cloning of a human cDNA that encodes a molecule having striking homology with Ras-specific GTPase-activating proteins (RasGAPs).
GO:0005515 protein binding	IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp...	MARK AS OVER ANNOTATED	Summary: This annotation is from a high-throughput mapping study of the TNF-alpha/NF-kappa B signaling pathway. The study used tandem affinity purification and mass spectrometry to identify protein-protein interactions. RASAL2 was identified as an interactor, though no specific binding partner was highlighted for RASAL2 specifically. Reason: While the experimental evidence for protein binding exists, "protein binding" (GO:0005515) is a vague, uninformative term that does not capture the functional significance of any interactions. High-throughput interaction studies identify many proteins, and this generic annotation does not provide insight into RASAL2's specific molecular role. More informative annotations such as specific binding partners or binding activities should be preferred. Supporting Evidence: PMID:14743216 Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference.
GO:0005515 protein binding	IPI PMID:15324660 Proteomic, functional, and domain-based analysis of in vivo ...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a proteomic study identifying 14-3-3 binding proteins. RASAL2 was identified as a 14-3-3 interactor, which is biologically relevant as 14-3-3 proteins are known to regulate RasGAP family members through phospho-dependent binding. This interaction may regulate RASAL2 localization or activity. Reason: While the 14-3-3 interaction is biologically meaningful and potentially relevant to RASAL2 regulation, the generic "protein binding" annotation fails to capture the specific nature of this interaction. A more informative term such as "14-3-3 protein binding" (GO:0071889) would be preferable if this interaction is to be annotated. Supporting Evidence: PMID:15324660 RESULTS: We have used mass spectrometry to analyze proteins that associate with 14-3-3 isoforms in HEK293 cells. PMID:36931259 14-3-3 proteins are highly conserved regulatory proteins that interact with hundreds of structurally diverse clients and act as central hubs of signaling networks.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: This annotation is from the first large-scale IP-MS study of protein-protein interactions in human cells. RASAL2 was identified as a prey protein in this high-throughput screen, but no specific interaction context was provided. Reason: High-throughput proteomics studies identify many protein interactions, but the generic "protein binding" annotation provides minimal biological insight. Without specific interaction partners or functional context, this annotation adds little to our understanding of RASAL2 function. Supporting Evidence: PMID:17353931 Mapping protein-protein interactions is an invaluable tool for understanding protein function. Here, we report the first large-scale study of protein-protein interactions in human cells using a mass spectrometry-based approach.
GO:0005515 protein binding	IPI PMID:18985028 Hepatitis C virus infection protein network.	MARK AS OVER ANNOTATED	Summary: This annotation derives from a study mapping protein interactions between Hepatitis C virus (HCV) proteins and human cellular proteins. RASAL2 was identified as interacting with one or more HCV proteins, suggesting potential involvement in host-virus interactions. Reason: While the HCV interaction is potentially interesting for understanding viral infection biology, the generic "protein binding" annotation is uninformative. The specific viral protein interaction and its functional consequence would be more meaningful if annotated with appropriate specificity. Supporting Evidence: PMID:18985028 A total of 314 protein-protein interactions between HCV and human proteins was identified by yeast two-hybrid and 170 by literature mining.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This annotation comes from a proteome-scale mapping of the human interactome using yeast two-hybrid methodology. While comprehensive, the study provides no specific functional context for RASAL2 interactions. Reason: Large-scale interactome mapping studies identify thousands of interactions but lack functional context. The generic "protein binding" term does not provide meaningful biological insight into RASAL2 function. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: This annotation derives from BioPlex 2.0, a large-scale affinity purification-mass spectrometry study of protein interactions in human cells. The study identified over 56,000 candidate interactions. Reason: While BioPlex is a valuable resource for discovering protein interactions, the generic "protein binding" annotation does not convey biological insight. Specific interaction partners and their functional relevance would be more informative. Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome, and constitutes, to our knowledge, the largest such network so far.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This annotation is from BioPlex 3.0, an extension of the BioPlex interactome mapping project. The study created cell-line-specific interaction networks using affinity purification-mass spectrometry. Reason: While the experimental evidence for protein binding exists, the generic "protein binding" term is uninformative. BioPlex 3.0 contains extensive interaction data, but without functional context, this annotation adds little to understanding RASAL2 biology. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: This annotation comes from the OpenCell project, which used endogenous tagging and affinity purification-mass spectrometry to map protein interactions. This represents high-quality interaction data from proteins expressed at endogenous levels. Reason: Although OpenCell provides high-quality interaction data from endogenously tagged proteins, the generic "protein binding" annotation remains uninformative. Specific interaction partners and their functional implications would be more valuable. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a study characterizing 14-3-3 protein interactions in human cells. RASAL2 was identified as a 14-3-3 client protein. 14-3-3 binding is biologically relevant as these proteins act as central hubs in signaling networks and may regulate RASAL2 activity through phosphorylation-dependent binding. Reason: The 14-3-3 interaction is biologically meaningful, but "protein binding" is too generic. A more specific term such as "14-3-3 protein binding" (GO:0071889) would better capture this interaction. The interaction suggests RASAL2 may be regulated by phosphorylation-dependent 14-3-3 binding. Supporting Evidence: PMID:36931259 14-3-3 proteins are highly conserved regulatory proteins that interact with hundreds of structurally diverse clients and act as central hubs of signaling networks.
GO:0002021 response to dietary excess	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is based on automatic transfer from orthologous genes in other species (Ensembl Compara). While RASAL2 has been implicated in metabolic signaling through its role in AMPK-dependent autophagy regulation and is associated with insulin resistance in some contexts [file:human/RASAL2/RASAL2-deep-research-perplexity.md], direct evidence for a role in response to dietary excess in humans is limited. Reason: RASAL2 has documented roles in metabolic signaling, particularly in autophagy regulation under nutrient stress conditions. However, this annotation represents a peripheral phenotypic association rather than a core function of RASAL2. The annotation is retained but marked as non-core due to limited direct evidence in humans. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 functions as a critical regulator of autophagy, a cellular degradation pathway essential for survival under nutrient stress and conditions of energy depletion.
GO:0009749 response to glucose	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is based on ortholog transfer. RASAL2 does respond to glucose levels through its interaction with the AMPK pathway. Under glucose deprivation, RASAL2 is phosphorylated at S351 by AMPK, leading to autophagy activation [file:human/RASAL2/RASAL2-deep-research-perplexity.md]. This represents a documented metabolic regulatory function. Reason: While RASAL2 does have documented involvement in glucose-responsive signaling through AMPK-dependent phosphorylation, this represents a metabolic regulatory role rather than a core molecular function. The annotation is retained as it reflects documented biology, but marked as non-core as it is not the primary function of RASAL2. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md Phosphorylation at serine 351 (S351) within the PH domain represents a target of AMPK-mediated phosphorylation under glucose-deprivation conditions, with this phosphorylation switching RASAL2 from a suppressor of autophagy under nutrient-rich conditions to a promoter of autophagy under nutrient-stress conditions. PMID:33563064 we found that 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.
GO:0010467 gene expression	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This annotation is based on ortholog transfer. While RASAL2 indirectly affects gene expression through its regulation of Ras-MAPK signaling, which modulates transcription factor activity, this is a very indirect and broad annotation. Reason: "Gene expression" is an extremely broad biological process. RASAL2's influence on gene expression is indirect, occurring through modulation of Ras-MAPK signaling and downstream transcription factors. This annotation does not capture the specific mechanism or provide useful biological insight. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md Loss or suppression of RASAL2 in human breast cancers and other tumor types results in elevated levels of active Ras-GTP and consequent hyperactivation of downstream MAPK/ERK signaling, leading to increased phosphorylation of ERK and enhanced phosphorylation of transcription factors that drive cell proliferation.
GO:0035264 multicellular organism growth	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This annotation is based on ortholog transfer. While RASAL2 affects cell proliferation through Ras pathway regulation, and mutations in RASAL2 have been associated with cancer growth, the specific annotation of "multicellular organism growth" is very broad and indirect. Reason: This is an extremely broad biological process annotation. RASAL2 influences cellular proliferation through Ras signaling modulation, but "multicellular organism growth" does not provide specific insight into RASAL2's molecular or cellular function. More specific annotations related to cell proliferation or Ras signaling would be more appropriate. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md Genetic studies in engineered mouse models provide in vivo validation of RASAL2's tumor-suppressive function, as Rasal2 mutations in luminal mammary cancer models dramatically enhance metastasis.
GO:0060612 adipose tissue development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is based on ortholog transfer. RASAL2 has been implicated in metabolic signaling and glucose responses, and adipose tissue development involves many signaling pathways. However, direct evidence for RASAL2 involvement in adipose tissue development in humans is limited. Reason: While there may be some involvement of RASAL2 in metabolic processes that affect adipose tissue, this annotation represents a peripheral phenotypic association rather than a core function. The annotation is retained based on ortholog evidence but marked as non-core. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 functions as a critical regulator of autophagy and metabolic stress responses.
GO:2000257 regulation of protein activation cascade	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is based on ortholog transfer. RASAL2 regulates the Ras-MAPK signaling cascade by modulating Ras GTPase activity. This annotation captures an aspect of RASAL2's signaling function, though it is quite general. Reason: While RASAL2 does regulate protein activation cascades through its modulation of Ras signaling, this annotation is somewhat redundant with the "regulation of intracellular signal transduction" annotation and does not provide additional specific insight. Retained as non-core as it accurately describes an aspect of RASAL2 function but is not the most informative annotation. Supporting Evidence: file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 functions as a negative regulator of the RAS-MAPK signaling pathway by catalyzing GTP hydrolysis of Ras proteins.
GO:0005829 cytosol	TAS Reactome:R-HSA-5658231	ACCEPT	Summary: This annotation indicates cytosolic localization based on Reactome pathway annotation. RASAL2 is predominantly cytoplasmic with enrichment at the plasma membrane upon calcium-dependent membrane recruitment through its C2 domains [file:human/RASAL2/RASAL2-deep-research-perplexity.md]. The cytosol annotation is accurate for the basal state of the protein. Reason: RASAL2 is documented to localize to the cytoplasm/cytosol, with translocation to the plasma membrane occurring upon activation via calcium-dependent C2 domain-mediated membrane binding. The cytosol annotation accurately reflects the resting state localization. Supporting Evidence: Reactome:R-HSA-5658231 The intrinsic GTPase activity of RAS proteins is stimulated by the GAP proteins, of which there are at least 10 in the human genome (reviewed in King et al, 2013). file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 localizes predominantly to the cytoplasm with enrichment at specific subcellular compartments including the plasma membrane and focal adhesion sites.
GO:0005829 cytosol	TAS Reactome:R-HSA-5658435	ACCEPT	Summary: This is a duplicate cytosol annotation from a different Reactome pathway reference (RAS GAPs bind RAS:GTP). The annotation is accurate and consistent with RASAL2's documented cytoplasmic localization. Reason: This annotation correctly identifies cytosolic localization of RASAL2. Although it duplicates the other cytosol annotation with a different reference, it is appropriate as it derives from a different Reactome pathway context (RAS binding versus GAP activity). Supporting Evidence: Reactome:R-HSA-5658435 These identified RAS GAP proteins are RASA1 (also known as p120 GAP), NF1, the GAP1 family (RASA2, RASA3, RASA4 and RASAL1) and the SYNGAP family (SYNGAP1, DAB2IP, RASAL2 and RASAL3).
GO:0005096 GTPase activator activity	TAS PMID:9877179 A novel human RasGAP-like gene that maps within the prostate...	ACCEPT	Summary: This TAS annotation is based on the original characterization of RASAL2 showing that it functions as a RasGAP. The study demonstrated that expression of RASAL2 in yeast defective in Ira2 (a RasGAP) complemented the loss of Ira2 function, providing functional evidence for GAP activity [PMID:9877179]. Reason: This annotation is based on direct experimental evidence demonstrating RASAL2 functions as a RasGAP. The yeast complementation assay provides strong functional evidence. This is a core molecular function of RASAL2. Supporting Evidence: PMID:9877179 Expression of the cDNA in Saccharomyces cerevisiae defective in one of two RasGAPs, Ira2, complemented loss of the Ira2 function, indicating that the cDNA product functions as a RasGAP.
GO:0007165 signal transduction	TAS PMID:9877179 A novel human RasGAP-like gene that maps within the prostate...	ACCEPT	Summary: This annotation indicates involvement in signal transduction based on the original RASAL2 characterization. As a RasGAP, RASAL2 modulates Ras signaling, which is a central component of signal transduction pathways downstream of receptor tyrosine kinases. Reason: RASAL2 functions as a negative regulator of Ras signaling, which is a core signal transduction pathway. The annotation accurately captures RASAL2's biological role and is supported by the original characterization paper and subsequent studies. Supporting Evidence: PMID:9877179 We report the molecular cloning of a human cDNA that encodes a molecule having striking homology with Ras-specific GTPase-activating proteins (RasGAPs). file:human/RASAL2/RASAL2-deep-research-perplexity.md RASAL2 functions as a negative regulator of the RAS-MAPK signaling pathway. file:human/RASAL2/RASAL2-deep-research-falcon.md By its RasGAP catalytic function, RASAL2 is placed upstream of major RAS effector pathways (e.g., ERK/MAPK, PI3K/AKT) as a negative regulator.