RASAL1 (RAS protein activator like 1) is a calcium-regulated GTPase-activating protein (GAP) of the GAP1 family that negatively regulates RAS signaling. The 804 amino acid protein contains two N-terminal C2 domains (C2A and C2B) that mediate Ca2+-dependent phospholipid binding, a central RasGAP catalytic domain with an essential arginine finger (Arg342), a pleckstrin homology (PH) domain for phosphoinositide binding, and a C-terminal Btk-type zinc finger domain. RASAL1 accelerates GTP hydrolysis on RAS proteins (including H-Ras, N-Ras, K-Ras), converting them from the active GTP-bound state to inactive GDP-bound form, thereby constraining RAF-MEK-ERK signaling. The protein cycles between cytosolic and plasma membrane-associated states in response to intracellular calcium oscillations - upon Ca2+ elevation, the C2 domains bind phosphatidylserine and the protein translocates to the membrane where it can access membrane-anchored RAS. Unlike the related CAPRI protein which shows sustained membrane association, RASAL1 tracks Ca2+ oscillations with rapid in-phase membrane translocations (half-maximal dissociation ~17 seconds). RASAL1 functions as a tumor suppressor frequently silenced by promoter hypermethylation in cancers including thyroid carcinoma, gastric cancer, and colorectal cancer. The protein also plays critical roles in organ fibrosis - TGF-beta-induced DNMT1-mediated promoter hypermethylation leads to persistent fibroblast activation in kidney fibrosis. RASAL1 is highly expressed in thyroid and adrenal medulla, with lower expression in brain, spinal cord, and trachea. Recent studies have identified neuronal functions including regulation of dendrite formation and microtubule dynamics through interactions with PKC, tubulin, and CaMKII.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: RASAL1 is a member of the GAP1 family of RasGAP proteins that accelerates GTP hydrolysis on RAS proteins. The protein contains a conserved GAP-related domain (GRD) with an arginine finger essential for catalysis [PMID:9751798]. Live-cell imaging confirms Ca2+-triggered GAP activity that correlates with membrane translocation [PMID:16009725]. Reason: This is a core molecular function of RASAL1. The IBA annotation is phylogenetically supported and consistent with extensive experimental evidence showing RASAL1 accelerates RAS GTP hydrolysis. Supporting Evidence: PMID:9751798 Sequence analysis of these two proteins revealed the presence of two N-terminal calcium-dependent phospholipid binding C2 domains, a conserved GAP related domain (GRD) and a C-terminal pleckstrin homology (PH) domain. PMID:16009725 RASAL is a Ca2+ sensor responding in-phase to repetitive Ca2+ signals by associating with the plasma membrane and deactivating Ras (Walker et al., 2004). file:human/RASAL1/RASAL1-deep-research-openai.md See deep research file for comprehensive analysis |
| GO:1902531 regulation of intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: RASAL1 negatively regulates RAS-mediated intracellular signaling by accelerating GTP hydrolysis on RAS proteins, thereby constraining downstream RAF-MEK-ERK signaling. This is a core biological process role. Reason: This IBA annotation is well-supported. RASAL1 regulates Ras signaling transduction as its primary cellular role. The annotation is at an appropriate level of specificity. Supporting Evidence: PMID:16009725 Each Ca2+-triggered GAP filters the Ca2+ signal differentially; this may convey alternative modes of information to regulate Ras and cell function. file:human/RASAL1/RASAL1-deep-research-falcon.md RASAL1 accelerates the intrinsic GTP hydrolysis of RAS, converting RAS-GTP to inactive RAS-GDP, thereby constraining downstream RAF-MEK-ERK signaling. |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation for GTPase activator activity is derived from automated methods including InterPro domain analysis (IPR037776 - RASAL_RasGAP). Reason: This is a correct annotation duplicating the IBA annotation. The IEA annotation is broader but not incorrect - the evidence from domain structure correctly identifies the core molecular function. Supporting Evidence: PMID:9751798 Sequence analysis of these two proteins revealed the presence of two N-terminal calcium-dependent phospholipid binding C2 domains, a conserved GAP related domain (GRD) and a C-terminal pleckstrin homology (PH) domain. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: RASAL1 is predominantly cytosolic at resting calcium levels but translocates to the plasma membrane upon Ca2+ elevation. Live-cell imaging studies directly demonstrate cytosolic localization. Reason: The cytosolic localization is well-supported by direct imaging studies. At resting Ca2+ levels, RASAL1 is diffusely cytosolic. Supporting Evidence: PMID:16009725 (A) Confocal images of HeLa cells expressing GFP-CAPRI (left) or GFP-RASAL (right) before (T = 0) or after 100 ΞΌM histamine stimulation file:human/RASAL1/RASAL1-deep-research-falcon.md In neurons, Rasal1 is diffusely cytosolic in soma/dendrites/axon but translocates to the plasma membrane in response to intracellular Ca2+ elevations. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: RASAL1 contains a Btk-type zinc finger domain (residues 674-710) with predicted zinc-binding residues at positions 682, 693, 694, and 704 based on PROSITE analysis (PRU00432). Reason: The Btk-type zinc finger is a well-characterized structural domain with clear zinc-binding residues annotated in UniProt. While experimental evidence for zinc binding is not directly cited, the domain structure strongly supports this function. Supporting Evidence: file:human/RASAL1/RASAL1-uniprot.txt ZN_FING 674..710 /note="Btk-type" /evidence="ECO:0000255|PROSITE-ProRule:PRU00432" |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: RASAL1 has been implicated in melanocyte differentiation through its C2 domain. Studies show forced expression of RASAL1 (referred to as SYT14L in the study) induces melanocyte differentiation-related markers. Reason: While RASAL1 has been shown to play a role in melanocyte differentiation, this represents a tissue-specific developmental function rather than the core molecular function of the protein. The primary role is as a RasGAP regulating Ras signaling. Supporting Evidence: PMID:23999003 Forced expression of full length SYT14L or the C2 domain of SYT14L induced a significant elongation of dendrite length accompanied by the induction of melanocyte differentiation-related markers, including melanin synthesis, tyrosinase catalytic activity and the expression of tyrosinase (TYR), tyrosinase related protein-1 (TRP-1) and TRP-2. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: RASAL1 participates in intracellular signal transduction by negatively regulating Ras-mediated signaling pathways. This is derived from InterPro Btk zinc finger domain annotation (IPR001562). Reason: This is a core biological process for RASAL1. The annotation is broader than GO:0046580 (negative regulation of Ras protein signal transduction) but is still accurate and acceptable for an IEA annotation. Supporting Evidence: PMID:9751798 The mammalian rasGAPs constitute a group of widely expressed proteins involved in the negative regulation of ras-mediated signaling. |
| GO:0046580 negative regulation of Ras protein signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: RASAL1 negatively regulates Ras signaling by accelerating GTP hydrolysis on Ras proteins. This is derived from the RASAL_RasGAP InterPro domain (IPR037776). Reason: This is the core biological process function of RASAL1. The protein accelerates Ras-GTP to Ras-GDP conversion, thereby negatively regulating Ras signaling. This annotation is highly specific and accurate. Supporting Evidence: PMID:16009725 RASAL is a Ca2+ sensor responding in-phase to repetitive Ca2+ signals by associating with the plasma membrane and deactivating Ras (Walker et al., 2004). file:human/RASAL1/RASAL1-deep-research-falcon.md RASAL1 accelerates the intrinsic GTP hydrolysis of RAS, converting RAS-GTP to inactive RAS-GDP, thereby constraining downstream RAF-MEK-ERK signaling. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: RASAL1 binds metal ions including calcium (via C2 domains) and zinc (via Btk zinc finger). This annotation is derived from UniProtKB metal-binding keyword mapping. Reason: The annotation is accurate but general. More specific annotations exist for zinc ion binding. The C2 domains also bind calcium ions as part of the regulatory mechanism, though this is primarily for membrane targeting rather than catalysis. Supporting Evidence: file:human/RASAL1/RASAL1-uniprot.txt COFACTOR Name=Ca(2+); Xref=ChEBI:CHEBI:29108 |
| GO:0071277 cellular response to calcium ion | IEA GO_REF:0000002 | ACCEPT | Summary: RASAL1 responds to intracellular calcium elevations by translocating from the cytosol to the plasma membrane. This Ca2+-dependent membrane recruitment is essential for its GAP activity. RASAL1 tracks Ca2+ oscillations with rapid in-phase membrane translocations [PMID:16009725]. Reason: This is a core regulatory mechanism for RASAL1 function. The C2 domains mediate Ca2+-dependent membrane translocation, coupling calcium signaling to Ras regulation. Extensive live-cell imaging studies support this annotation. Supporting Evidence: PMID:16009725 RASAL also tracks Ca2+ oscillations (Walker et al., 2004). file:human/RASAL1/RASAL1-deep-research-falcon.md RASAL1 is diffusely cytosolic in soma/dendrites/axon but translocates to the plasma membrane in response to intracellular Ca2+ elevations; the C2A domain binds phosphatidylserine and C2B binds phosphoinositides, supporting Ca2+-dependent membrane association. |
| GO:1903861 positive regulation of dendrite extension | IDA PMID:23999003 SYT14L, especially its C2 domain, is involved in regulating ... | KEEP AS NON CORE | Summary: The annotation is based on a study showing that C2 domain-containing proteins including RASAL1 (referred to as SYT14L in the publication) regulate dendrite outgrowth in melanocytes. Overexpression induced dendrite lengthening. Reason: While the IDA evidence supports involvement in dendrite extension, this is a tissue-specific developmental function in melanocytes rather than the core molecular function. The study focused on the C2 domain contribution to dendrite formation. Recent neuronal studies also support microtubule regulation roles. Supporting Evidence: PMID:23999003 Forced expression of full length SYT14L or the C2 domain of SYT14L induced a significant elongation of dendrite length accompanied by the induction of melanocyte differentiation-related markers, including melanin synthesis, tyrosinase catalytic activity and the expression of tyrosinase (TYR), tyrosinase related protein-1 (TRP-1) and TRP-2. file:human/RASAL1/RASAL1-deep-research-falcon.md Deurloo et al. showed that neuronal Rasal1 directly interacts with PKC, tubulin, and CaMKII; stabilizes microtubules via tubulin modifications; inhibits dendritic outgrowth/branching. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658231 | ACCEPT | Summary: Reactome pathway annotation for RAS GAPs stimulating RAS GTPase activity. RASAL1 is depicted as a cytosolic protein that can associate with the membrane. Reason: Cytosolic localization is well-supported. This Reactome annotation correctly places RASAL1 in the cytosol as part of the Ras regulation pathway. Supporting Evidence: PMID:16009725 (A) Confocal images of HeLa cells expressing GFP-CAPRI (left) or GFP-RASAL (right) before (T = 0) or after 100 ΞΌM histamine stimulation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658435 | ACCEPT | Summary: Reactome pathway annotation for RAS GAPs binding RAS:GTP. RASAL1 is cytosolic and translocates to interact with membrane-anchored Ras. Reason: Cytosolic localization is well-supported. Duplicate of other cytosol annotations but valid. Supporting Evidence: PMID:16009725 The experiments confirmed that CAPRI has little basal GAP activity in resting cells and is acutely regulated by Ca2+ mobilization. |
| GO:0005829 cytosol | IDA PMID:16009725 CAPRI and RASAL impose different modes of information proces... | ACCEPT | Summary: Direct imaging of GFP-RASAL in live cells demonstrated cytosolic localization at resting Ca2+ levels, with Ca2+-dependent translocation to the plasma membrane. Reason: This is high-quality direct experimental evidence for cytosolic localization. The study used GFP-tagged RASAL1 with confocal and TIRFM imaging. Supporting Evidence: PMID:16009725 (A) Confocal images of HeLa cells expressing GFP-CAPRI (left) or GFP-RASAL (right) before (T = 0) or after 100 ΞΌM histamine stimulation |
| GO:0005886 plasma membrane | IDA PMID:16009725 CAPRI and RASAL impose different modes of information proces... | ACCEPT | Summary: Live-cell imaging demonstrated Ca2+-dependent translocation of GFP-RASAL1 to the plasma membrane. RASAL1 tracks Ca2+ oscillations with rapid in-phase membrane translocations (half-maximal dissociation ~17 seconds). TIRFM imaging provided high-resolution confirmation. Reason: This is high-quality direct experimental evidence. The study clearly demonstrates activity-dependent plasma membrane localization in response to calcium elevation. Note the annotation uses 'colocalizes_with' qualifier, which is appropriate for transient association. Supporting Evidence: PMID:16009725 Half-maximal dissociation back to the cytosol was >280 s, contrasting with half-maximal dissociation of 17 s for GFP-RASAL and 13 s for GFP-PKCΞ³ (Fig PMID:16009725 GFP-RASAL exhibited rapid oscillations in parallel experiments (Fig |
| GO:0005096 GTPase activator activity | TAS PMID:9751798 Restricted tissue expression pattern of a novel human rasGAP... | ACCEPT | Summary: The original characterization paper identified RASAL1 as a novel rasGAP based on sequence similarity to the GAP1 family and domain architecture including a conserved GAP-related domain. Reason: This TAS annotation is well-founded. The paper characterizes RASAL1 as having a conserved GAP-related domain and being similar to known RasGAP proteins. Supporting Evidence: PMID:9751798 In this study we have isolated a novel human gene, RASAL (Ras GTPase-activating-like) and its murine ortholog, MRASAL which are most similar to the GAP1 family of rasGAP proteins, based upon the presence and organization of specific conserved domains. |
| GO:0005543 phospholipid binding | TAS PMID:9751798 Restricted tissue expression pattern of a novel human rasGAP... | ACCEPT | Summary: RASAL1 contains two N-terminal C2 domains that mediate calcium-dependent phospholipid binding. This enables membrane targeting upon Ca2+ elevation. Reason: The C2 domains are well-characterized calcium-dependent phospholipid binding domains. This function is essential for the Ca2+-regulated membrane translocation mechanism. Supporting Evidence: PMID:9751798 Sequence analysis of these two proteins revealed the presence of two N-terminal calcium-dependent phospholipid binding C2 domains, a conserved GAP related domain (GRD) and a C-terminal pleckstrin homology (PH) domain. PMID:16009725 It seemed likely that electrostatic and lipid headgroup interactions were necessary for C2 domainβdriven translocation, as is the case for other C2 domainβcontaining Ca2+ sensors (Rizo and Sudhof, 1998) |
| GO:0007165 signal transduction | TAS PMID:9751798 Restricted tissue expression pattern of a novel human rasGAP... | ACCEPT | Summary: RASAL1 participates in ras-mediated signal transduction as a negative regulator. This broad annotation encompasses its role in the Ras-MAPK pathway. Reason: This is accurate but represents a broader annotation than the more specific GO:0046580 (negative regulation of Ras protein signal transduction). Both annotations are acceptable as they are at different levels of specificity. Supporting Evidence: PMID:9751798 The mammalian rasGAPs constitute a group of widely expressed proteins involved in the negative regulation of ras-mediated signaling. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000043 | NEW | Summary: RASAL1 contains two C2 domains with multiple predicted calcium-binding residues. UniProt annotates calcium binding sites at positions 21, 27, 74, 76, 82, 149, 155, 202, 204, and 210 based on PROSITE pattern PRU00041. Reason: This annotation is missing from the current GOA file but is strongly supported by both domain analysis and functional studies. The C2 domains require Ca2+ binding for membrane translocation function. Proposed replacements: calcium ion binding Supporting Evidence: file:human/RASAL1/RASAL1-uniprot.txt COFACTOR Name=Ca(2+); Xref=ChEBI:CHEBI:29108 BINDING 21 /ligand="Ca(2+)" /ligand_id="ChEBI:CHEBI:29108" PMID:16009725 We showed previously that the C2A and C2B domains of CAPRI in tandem (C2AB) are necessary and sufficient for sensing an increase in cytosolic Ca2+ (Lockyer et al., 2001). |
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Download this section (compressed HTML)Q: Does RASAL1 have GAP activity toward Rap1 GTPase in addition to Ras proteins, as suggested for some GAP1 family members?
Q: What is the relative contribution of the PH domain versus C2 domains for membrane targeting specificity?
Q: Are there tissue-specific functions of RASAL1 in thyroid and adrenal medulla where it is most highly expressed?
Q: What is the mechanistic relationship between RASAL1 and tubulin/microtubule dynamics identified in neuronal studies?
Experiment: In vitro GAP assays with purified RASAL1 against different Ras family members to establish substrate specificity
Hypothesis: RASAL1 may have broader substrate specificity including Rap1 GTPase
Experiment: Structural studies of the C2 domains bound to calcium and phospholipids
Hypothesis: Structural basis of Ca2+-dependent membrane translocation
Experiment: Analysis of RASAL1 methylation status as a biomarker in fibrosis and cancer
Hypothesis: RASAL1 promoter methylation correlates with disease progression
Experiment: CRISPR knockout studies in neuronal cells to clarify dendritic function
Hypothesis: RASAL1 regulates dendritic morphology through microtubule dynamics
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