RASGEF1A (RasGEF domain family member 1A) is a cytoplasmic guanine nucleotide exchange factor of the CDC25-homology family, with an N-terminal Ras exchanger motif (REM, RasGEF_N) and a C-terminal catalytic Ras-GEF (CDC25) domain. It activates small GTPases by catalysing GDP release and GTP loading. Biochemical assays with purified human RasGEF1A identified it as a highly specific exchange factor for Rap2, with no activity on Rap1 or Ras-subfamily GTPases, whereas an earlier study reported in vitro exchange on H-, K- and N-Ras and increased Ras activity and cell motility on overexpression; the physiological substrate is therefore not settled. The human gene is expressed in brain and spinal cord. Its subcellular site of action has not been determined experimentally.
Summary: Guanyl-nucleotide exchange factor activity from the combined IEA pipeline (human ortholog, Ras-GEF domain InterPro entries, PANTHER node). The donkey protein is in PANTHER subfamily PTHR23113:SF172 with human RASGEF1A, whose exchange activity has been shown with purified protein.
Reason: Core function. The donkey protein sits in the same PANTHER subfamily (SF172, RAS-GEF DOMAIN-CONTAINING FAMILY MEMBER 1A) as human Q8N9B8, shares 96% identity with it and has complete REM and CDC25 domains. GEF activity is also the eukaryote-wide PAINT IBD at PTN000560991, whose seeds include Q8N9B8. Both human papers demonstrate exchange activity, although they disagree on the substrate, so the generic GEF term is the right level.
Using purified RasGEF1A and RasGEF1B proteins, as well as Ras family proteins, we established that RasGEF1A and RasGEF1B function as very specific exchange factors for Rap2
Summary: TreeGrafter transfer of plasma membrane from PAINT node PTN007734601; the node's seeds are other family members (SOS, RasGRF/RasGRP-type GEFs and invertebrate/yeast relatives), not RASGEF1A. Human RASGEF1A has this term only by IBA.
Reason: RASGEF1A has no transmembrane segment, lipid anchor or membrane-binding domain annotated, and no experimental localization exists for any RASGEF1 subfamily member in the records examined (human has only Reactome cytosol, TAS). The donkey protein falls inside the clade PAINT curators assigned, so the inference is not demonstrably wrong; kept as a plausible but unestablished location.
Supporting Evidence:
file:EQUAS/RASGEF1A/RASGEF1A-uniprot.txt
PTHR23113:SF172; RAS-GEF DOMAIN-CONTAINING FAMILY MEMBER 1A
GO:0007264 small GTPase-mediated signal transduction
IEA GO_REF:0000002
ACCEPT
Summary: InterPro2GO mapping from the Ras-GEF catalytic domain. A GEF performs the activating step of small GTPase-mediated signalling.
Reason: Correct and, for now, as precise as the evidence allows. Purified human RasGEF1A acts specifically on Rap2 (which would be Rap protein signal transduction, GO:0032486), while an earlier study reported exchange on H-, K- and N-Ras (Ras protein signal transduction, GO:0007265). In GO these two terms are siblings under this term, and the physiological substrate has not been established in cells, so this parent term is the appropriate process term and is used in core_functions.
Using purified RasGEF1A and RasGEF1B proteins, as well as Ras family proteins, we established that RasGEF1A and RasGEF1B function as very specific exchange factors for Rap2
Summary: TreeGrafter transfer of Ras protein signal transduction from the eukaryote-level PAINT node PTN000560991. The seeds for this term at that node are SOS-type and yeast/amoeba GEFs; Q8N9B8 is a seed for GEF activity at that node but not for this process term.
Reason: Ras-subfamily specificity is disputed for RASGEF1A. Ura et al. 2006 reported exchange on H-, K- and N-Ras and increased Ras activity on overexpression, but Yaman et al. 2009 (purified proteins, Wittinghofer laboratory) found RasGEF1A to be Rap2-specific and explicitly inactive on Ras-subfamily members. The deep PAINT node is a reasonable family-level default, but subfamily-specific data point away from classical Ras. Retained as non-core; the core process is recorded at the parent small GTPase-mediated signal transduction.
Summary: Ensembl orthology transfer from the human IDA annotation (Ura et al. 2006), based on increased Transwell and wound-healing motility of COS7 cells overexpressing RASGEF1A.
Reason: Overexpression-driven motility in a heterologous cell line is a downstream cellular outcome of GTPase activation, not evidence of a dedicated role in cell migration. The orthology relationship (same PANTHER subfamily) is sound and the curator read the full paper, so the annotation is kept as non-core.
COS7 cells expressing exogenous RASGEF1A showed enhanced cellular motility in Transwell and wound-healing assays
GO:0046579 positive regulation of Ras protein signal transduction
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Ensembl orthology transfer from a human IDA annotation (FlyBase). Overexpressed RASGEF1A increased Ras activity in cells.
Reason: Supported by the cell-based Ras activation reported by Ura et al. 2006, but contradicted for direct Ras exchange by the purified-protein study of Yaman et al. 2009; the Ras effect may be indirect. The human annotation was made from full text we cannot see, so it is not removed; kept as non-core.
exogenous RASGEF1A expression increased the activity of Ras
Core Functions
Guanine nucleotide exchange factor that activates small GTPases through its CDC25-type Ras-GEF domain; the best biochemical evidence (purified human protein) indicates specificity for Rap2, with reported but disputed activity on H-, K- and N-Ras.
Using purified RasGEF1A and RasGEF1B proteins, as well as Ras family proteins, we established that RasGEF1A and RasGEF1B function as very specific exchange factors for Rap2
Q: Is RASGEF1A a Rap2-specific GEF in cells, as purified-protein assays indicate, or does it also activate H-, K- and N-Ras as reported from cholangiocarcinoma work?
Q: Where in the cell does RASGEF1A act, given that it lacks any annotated membrane anchor and the plasma membrane term is inferred only from distant family members?
Suggested Experiments
Experiment: Endogenous tagging of RASGEF1A in neural cells to determine subcellular localization, combined with GTP-loading pull-down assays for Rap2 and H/K/N-Ras after RASGEF1A depletion, and side-by-side in vitro exchange assays with purified RASGEF1A on Rap2 versus K-Ras.
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of the single ProtNLM2 GO prediction for donkey RASGEF1A (A0A9L0J8J4), judged against the donkey GOA record (guanyl-nucleotide exchange factor activity, plasma membrane, small GTPase-mediated signal transduction, Ras protein signal transduction, cell migration, positive regulation of Ras protein signal transduction), the re-reviewed donkey gene review, the human ortholog Q8N9B8 (exchange activity shown with purified protein, Rap2-specific in one study and Ras-active in another) and a donkey-human alignment (96% identity, both GEF domains intact). The prediction, small GTPase-mediated signal transduction, is correct and already carried by the donkey gene (CNN). Non-GO ProtNLM2 output, not scored - subcellular location 'Nucleus', which has no support in the human or donkey records (human has cytosol by Reactome TAS and plasma membrane by IBA only).
Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.
GO:0007264 small GTPase-mediated signal transductionGO_BP
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: Purified human RasGEF1A has guanine nucleotide exchange activity on small GTPases, specifically on Rap2 in one study and on H-, K- and N-Ras in another, so it acts at the activating step of small GTPase-mediated signalling whichever substrate is physiological. The donkey protein is in the same PANTHER subfamily (PTHR23113:SF172) as human Q8N9B8 and keeps the complete REM and catalytic Ras-GEF domains at 96% identity. The donkey gene already carries this exact term (InterPro2GO), which the gene review accepts as the core process term, so the prediction is correct but not novel. It is not less specific than a supported annotation, because the more specific Ras protein signal transduction is disputed for this gene and Rap2 signalling falls under a sibling term.
Supporting Evidence:
PMID:19645719: "Using purified RasGEF1A and RasGEF1B proteins, as well as Ras family proteins, we established that RasGEF1A and RasGEF1B function as very specific exchange factors for Rap2"
PMID:17121879: "RASGEF1A protein has a guanine nucleotide exchange activity to K-RAS, H-RAS, and N-RAS proteins in vitro"