Existing Annotations Review

Core Functions

RAS2 serves as the primary regulator of cAMP/PKA signaling pathway, acting as a molecular switch that cycles between GTP-bound active and GDP-bound inactive states. In the active state, RAS2-GTP binds to and activates adenylate cyclase (CYR1), increasing cellular cAMP levels. This triggers cAMP-dependent protein kinase (PKA) activation, which phosphorylates downstream targets controlling nutrient-dependent growth, glucose metabolism, stress resistance, and replicative lifespan determination.

Molecular Function:

GTPase activity

Directly Involved In:

Ras protein signal transduction cellular response to glucose starvation

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:6438624
A product of yeast RAS2 gene is a guanine nucleotide binding protein
PMID:8106517
Biochemical characterization of yeast RAS2 reveals GTPase activity and interactions with GTPase-activating proteins
PMID:15016820
The Ras/cAMP-dependent protein kinase signaling pathway regulates nutrient starvation response

RAS2 functions in morphogenetic signaling through the Cdc42/MAPK pathway to regulate cell division polarity and pseudohyphal growth. Upon nutrient starvation, activated RAS2 signals through Cdc42 and the MAPK cascade (Ste20/Ste11/Ste7) to induce filamentous growth and coordinate unipolar budding pattern characteristic of pseudohyphae. This allows nutrient foraging in diploid cells.

Molecular Function:

GTPase activity

Directly Involved In:

positive regulation of pseudohyphal growth establishment or maintenance of cell polarity

Supporting Evidence:

PMID:1547504
Unipolar cell divisions in yeast S. cerevisiae lead to filamentous growth regulated by starvation and RAS
PMID:8643578
Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth

RAS2 regulates protein localization to the bud neck and cell division machinery. RAS2-GTP recruits and anchors mitotic exit regulators (including Lte1) to the bud cortex in a Cdc42-dependent manner, controlling cell polarity and ensuring proper cytokinesis.

Molecular Function:

GTPase activity

Directly Involved In:

protein localization to bud neck regulation of protein localization

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:12782684
Ras recruits mitotic exit regulator Lte1 to the bud cortex in budding yeast
PMID:15917658
Ras and the Rho effector Cla4 collaborate to target and anchor Lte1 at the bud cortex

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11805837

Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry.

PMID:11914276

Subcellular localization of the yeast proteome.

PMID:12782684

Ras recruits mitotic exit regulator Lte1 to the bud cortex in budding yeast.

PMID:15016820

The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae.

PMID:1547504

Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS.

PMID:15917658

Ras and the Rho effector Cla4 collaborate to target and anchor Lte1 at the bud cortex.

PMID:16292676

Increased phosphoglucomutase activity suppresses the galactose growth defect associated with elevated levels of Ras signaling in S. cerevisiae.

PMID:16554755

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.

PMID:16622836

The plasma membrane proteome of Saccharomyces cerevisiae and its response to the antifungal calcofluor.

PMID:20162532

Chemical inhibition of CaaX protease activity disrupts yeast Ras localization.

PMID:21073870

Feedback regulation of Ras2 guanine nucleotide exchange factor (Ras2-GEF) activity of Cdc25p by Cdc25p phosphorylation in the yeast Saccharomyces cerevisiae.

PMID:21457714

The membrane localization of Ras2p and the association between Cdc25p and Ras2-GTP are regulated by protein kinase A (PKA) in the yeast Saccharomyces cerevisiae.

PMID:21925385

The cAMP-dependent protein kinase signaling pathway is a key regulator of P body foci formation.

PMID:22575457

Localization of Ras signaling complex in budding yeast.

PMID:23127800

Live-cell imaging of endogenous Ras-GTP shows predominant Ras activation at the plasma membrane and in the nucleus in Saccharomyces cerevisiae.

PMID:23831759

Mapping the functional yeast ABC transporter interactome.

PMID:24769239

Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae.

PMID:2558958

Isolation and characterization of temperature-sensitive mutations in the RAS2 and CYR1 genes of Saccharomyces cerevisiae.

PMID:26928762

One library to make them all: streamlining the creation of yeast libraries via a SWAp-Tag strategy.

PMID:6438624

A product of yeast RAS2 gene is a guanine nucleotide binding protein.

PMID:8106517

Biochemical characterization of yeast RAS2 mutants reveals a new region of ras protein involved in the interaction with GTPase-activating proteins.

PMID:8643578

Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae.

file:yeast/RAS2/RAS2-deep-research-falcon.md

Falcon deep research report on RAS2 (Saccharomyces cerevisiae)

RAS2 (Ras2p) is a 322-residue Ras-family small GTPase that acts as a molecular switch, cycling between an inactive GDP-bound state and an active GTP-bound state under control of upstream GEFs and GAPs.

"Ras2p cycles between an **inactive GDP-bound** state and an **active GTP-bound** state. This GTPase cycle is central to Ras2p’s signaling role and is controlled by upstream regulators (GEFs and GAPs)."
The primary biochemical function of RAS2 is activation of adenylate cyclase (Cyr1/CDC35) to produce cAMP, which binds Bcy1 to activate the PKA catalytic subunits Tpk1/2/3, defining the core Ras-cAMP-PKA pathway that controls growth and metabolism.

"In budding yeast, both Ras1p and Ras2p act upstream of **adenylate cyclase (Cyr1/CDC35)** to stimulate **cAMP** production; cAMP then binds the regulatory subunit **Bcy1** to activate **PKA catalytic subunits Tpk1/2/3**, establishing the core **Ras–cAMP–PKA** pathway that controls growth and metabolism."
RAS2-GTP levels are set by the GEF Cdc25 (required for glucose-induced Ras-GTP increase) and the GAPs Ira1 and Ira2, which stimulate intrinsic GTP hydrolysis and negatively regulate cAMP output.

"The primary Ras GEF **Cdc25** promotes GDP→GTP exchange on Ras proteins and is required for the **glucose-induced increase in Ras-GTP**; temperature-sensitive cdc25 mutants show reduced intracellular cAMP and reduced adenylate cyclase activity"
RAS2 membrane targeting depends on CAAX processing: it is farnesylated at Cys319 and palmitoylated at Cys318; farnesylation is required for plasma membrane localization and effector recruitment, and loss of palmitoylation (C318S) mislocalizes Ras2p to the cytoplasm.

"Ras2p is reported to be **farnesylated at Cys319** and **palmitoylated at Cys318**; **farnesylation** is required for efficient **plasma membrane localization** and effector recruitment, whereas loss of palmitoylation (C318S) mislocalizes Ras2p to the cytoplasm in the cited work."
Activation of Cyr1 by RAS2 occurs at the plasma membrane, although RAS2 and its partners are also observed on endomembranes, contacting the ER and accumulating at mitochondria under nutrient depletion, with nuclear active Ras2 reported in invasive growth contexts.

"While Ras2p and its regulators/partners have been observed on **endomembranes**, the activation of Cyr1 by Ras2 that drives cAMP production is described as occurring at the **plasma membrane**."
RAS2 is a dominant controller of glucose-responsive transcription, accounting for nearly ~90% of the transcriptional changes observed upon glucose addition.

"Ras2-driven Ras/cAMP/PKA signaling is described as accounting for **nearly ~90%** of the transcriptional changes observed upon glucose addition, placing Ras2 as a dominant controller of glucose-responsive transcriptional reprogramming."
RAS1 and RAS2 double loss is lethal while single deletions are viable on glucose; ras2Delta strains show defects in growth on nonfermentable carbon sources.

"Yeast has two Ras genes (**RAS1** and **RAS2**). Loss of both is **lethal**, consistent with an essential requirement for Ras-dependent activation of the cAMP/PKA pathway, while single deletions are viable under standard glucose conditions."
RAS2 influences filamentous/invasive growth and cell-fate decisions, linking Ras2/cAMP/PKA signaling to differentiation outputs including Flo8-linked programs.

"Ras2 influences filamentous/invasive growth and broader “cell fate” decisions; the corpus links Ras2/cAMP/PKA signaling to differentiation outputs (including Flo8-linked programs) and provides a localization-focused treatment of nuclear active Ras2 in invasive growth."
RAS2 is best interpreted as a central nutrient-state integrator, positioned at the interface between extracellular nutrient cues (especially glucose) and broad intracellular programs for growth, stress protection, and differentiation.

"Ras2p is best interpreted as a **central nutrient-state integrator**: upstream regulators (Cdc25; Ira1/2; additional modulators such as Gpb1/2) determine the fraction of Ras2p in the GTP-bound state, which is then transduced primarily by Cyr1 into cAMP dynamics and PKA activation."

Deep Research

Falcon

(RAS2-deep-research-falcon.md)

Research Report: *Saccharomyces cerevisiae* **RAS2** (UniProt **P01120**; ORF **YNL098C**) — Functional Annotation Falcon Edison Scientific Literature 11 citations 1 artifacts 2026-05-30T10:08:54.579763

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Saccharomyces cerevisiae RAS2 (UniProt P01120; ORF YNL098C) — Functional Annotation

1. Gene/Protein identity verification (critical disambiguation)

The target is Saccharomyces cerevisiae (S288c) RAS2, encoding Ras2p, a 322 amino-acid Ras-family small GTPase with conserved GTP-binding/GTPase motifs and a C-terminal CAAX box for lipid modification and membrane association, matching the UniProt entry P01120 and the canonical yeast Ras2 signaling module. (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)

2. Key concepts, definitions, and current understanding

2.1 Ras2p is a small GTPase “molecular switch”

Ras2p cycles between an inactive GDP-bound state and an active GTP-bound state. This GTPase cycle is central to Ras2p’s signaling role and is controlled by upstream regulators (GEFs and GAPs). (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)

2.2 Primary biochemical function: activation of adenylate cyclase → cAMP → PKA

In budding yeast, both Ras1p and Ras2p act upstream of adenylate cyclase (Cyr1/CDC35) to stimulate cAMP production; cAMP then binds the regulatory subunit Bcy1 to activate PKA catalytic subunits Tpk1/2/3, establishing the core Ras–cAMP–PKA pathway that controls growth and metabolism. (tamanoi2011rassignalingin pages 1-2, dresel2021therolesof pages 31-36)

A structural/functional feature of the yeast effector is that Cyr1 is ~2,026 amino acids and contains a Ras-associating region enabling Ras-dependent activation. (dresel2021therolesof pages 31-36, tamanoi2011rassignalingin pages 1-2)

2.3 Pathway logic: signal amplification and termination

Ras2p’s effect on cAMP is shaped not only by Ras2 activity state but also by cAMP turnover through phosphodiesterases Pde1 and Pde2, which degrade cAMP and thereby constrain PKA signaling output. (dresel2021therolesof pages 31-36, tamanoi2011rassignalingin pages 1-2)

3. Regulators, effectors, and mechanistic network (authoritative evidence)

3.1 Positive regulators (GEFs): Cdc25 and Sdc25

The primary Ras GEF Cdc25 promotes GDP→GTP exchange on Ras proteins and is required for the glucose-induced increase in Ras-GTP; temperature-sensitive cdc25 mutants show reduced intracellular cAMP and reduced adenylate cyclase activity, highlighting Cdc25 as a proximal activator of Ras2-driven cAMP signaling. (broggi2013studiesonactive pages 22-26)

3.2 Negative regulators (GAPs): Ira1 and Ira2

Ira1 and Ira2 stimulate Ras intrinsic GTP hydrolysis (GAP activity) and thus negatively regulate Ras2-driven cAMP output; ira mutants show stress-related phenotypes consistent with Ras/cAMP/PKA hyperactivation. (broggi2013studiesonactive pages 22-26, tamanoi2011rassignalingin pages 2-3)

3.3 Additional modulators: Gpb1/Gpb2 (Kelch-repeat proteins)

Kelch-repeat proteins Gpb1/Gpb2 are described as inhibitors of Ras signaling via association with Ira1/Ira2 and have also been linked to regulation of PKA activity, positioning them as higher-level modulators of Ras2→cAMP/PKA signaling. (tamanoi2011rassignalingin pages 2-3, dresel2021therolesof pages 144-149)

3.4 Effector complex organization and scaffolding concepts

Evidence summarized in the retrieved corpus supports that adenylate cyclase can act within a multiprotein assembly: Ira1 is discussed as potentially contributing a structural role in anchoring adenylate cyclase at membranes and participating in an oligomeric membrane-associated complex with Ras. (broggi2013studiesonactive pages 26-30)

4. Subcellular localization and where Ras2p acts

4.1 Lipid modification and membrane targeting

Ras2p membrane association is controlled by C-terminal CAAX processing and lipidation. Ras2p is reported to be farnesylated at Cys319 and palmitoylated at Cys318; farnesylation is required for efficient plasma membrane localization and effector recruitment, whereas loss of palmitoylation (C318S) mislocalizes Ras2p to the cytoplasm in the cited work. (broggi2013studiesonactive pages 22-26)

Ras CAAX processing includes farnesylation followed by AAX proteolysis, methylation, and palmitoylation, and farnesylation targets Ras proteins to ER/Golgi membranes for processing en route to the plasma membrane. (broggi2013studiesonactive pages 17-22)

4.2 Site of signaling output: plasma membrane, with endomembrane pools

While Ras2p and its regulators/partners have been observed on endomembranes, the activation of Cyr1 by Ras2 that drives cAMP production is described as occurring at the plasma membrane. (dresel2021therolesof pages 31-36)

4.3 Non-canonical/extended localization: nucleus, ER contact, mitochondria

The retrieved corpus also describes broader compartmentalization: Cdc25 itself is described as having nuclear localization features, and Ras2p has been reported to contact the ER and accumulate at mitochondria under nutrient depletion; a dissertation-level source in the corpus further focuses on evidence for nuclear active Ras2 in invasive growth contexts. (broggi2013studiesonactive pages 22-26, dresel2021therolesof pages 31-36)

5. Biological processes and phenotypes (functional evidence)

5.1 Essentiality and core growth roles

Yeast has two Ras genes (RAS1 and RAS2). Loss of both is lethal, consistent with an essential requirement for Ras-dependent activation of the cAMP/PKA pathway, while single deletions are viable under standard glucose conditions. (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)

5.2 Carbon source utilization and respiratory growth

RAS2 contributes to growth on nonfermentable carbon sources: ras2Δ is associated with defects in growth on nonfermentable substrates, and Ras1 overexpression can suppress some ras2Δ defects under these conditions. (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)

5.3 Glucose sensing and transcriptional control (quantitative-scale statement)

Ras2-driven Ras/cAMP/PKA signaling is described as accounting for nearly ~90% of the transcriptional changes observed upon glucose addition, placing Ras2 as a dominant controller of glucose-responsive transcriptional reprogramming. (dresel2021therolesof pages 31-36)

5.4 Stress resistance, storage carbohydrates, and feedback regulation

Ras/cAMP/PKA tuning strongly affects stress phenotypes and storage carbohydrates (trehalose/glycogen). Decreased cAMP signaling (e.g., in upstream pathway reductions) is associated with increased heat resistance and increased trehalose/glycogen and STRE-controlled gene expression, whereas hyperactive Ras signaling (e.g., Ras2Val19) is associated with decreased glycogen and stress sensitivities. (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 26-30)

Post-translational feedback contributes: Ras2p phosphorylation at Ser214 is described as feedback regulation; an S214A mutant increases cAMP, decreases glycogen, and increases heat-shock sensitivity. (tamanoi2011rassignalingin pages 2-3)

A separate phosphorylation site, Ser225, is described as altering Ras2 localization and being linked to quiescence entry through aberrant Ras/cAMP/PKA signaling. (dresel2021therolesof pages 18-22)

5.5 Differentiation programs: filamentous/invasive growth

Ras2 influences filamentous/invasive growth and broader “cell fate” decisions; the corpus links Ras2/cAMP/PKA signaling to differentiation outputs (including Flo8-linked programs) and provides a localization-focused treatment of nuclear active Ras2 in invasive growth. (dresel2021therolesof pages 31-36, broggi2013studiesonactive pages 22-26)

6. Recent developments and latest research (2023–2024 emphasis and evidence limits)

Within the documents successfully retrieved for full-text evidence in this run, the most Ras2-specific mechanistic content comes from authoritative but older syntheses (e.g., Tamanoi 2011) and a comprehensive 2021 synthesis/dissertation text (dresel2021therolesof pages 31-36, broggi2013studiesonactive pages 22-26, tamanoi2011rassignalingin pages 1-2). Tool-based search did identify recent 2024 reviews relevant to yeast nutrient/stress signaling and cAMP/PKA pathway context, but their full-text evidence was not available in the current retrieved corpus for Ras2-specific citation, so they are not used here to support new Ras2-specific claims.

Accordingly, the “current understanding” section above reflects the highest-confidence, well-supported Ras2 mechanisms; 2023–2024 Ras2-specific updates could not be incorporated with the required evidence standard in this run.

7. Current applications and real-world implementations

7.1 Fermentation and industrially relevant nutrient utilization

The Ras2 pathway is practically relevant in fermentation settings because the Cdc25/Ras/cAMP-PKA signaling axis regulates nutrient utilization programs. The retrieved corpus includes evidence that this pathway regulates proline utilization in a wine fermentation model, supporting real-world relevance of Ras2-pathway tuning to fermentation performance. (tamanoi2011rassignalingin pages 2-3)

7.2 Robustness traits relevant to industrial conditions

Because fermentation performance depends on stress tolerance, Ras2’s control of heat shock and storage carbohydrate allocation (trehalose/glycogen) provides a mechanistic basis for engineering or selecting strains with altered robustness, even where explicit engineering interventions were not detailed in the accessible full text. (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 26-30)

8. Expert synthesis and authoritative interpretation

Ras2p is best interpreted as a central nutrient-state integrator: upstream regulators (Cdc25; Ira1/2; additional modulators such as Gpb1/2) determine the fraction of Ras2p in the GTP-bound state, which is then transduced primarily by Cyr1 into cAMP dynamics and PKA activation. This places Ras2p at the interface between extracellular nutrient cues (especially glucose availability) and broad intracellular programs (growth rate, stress protection, and differentiation). (dresel2021therolesof pages 31-36, tamanoi2011rassignalingin pages 1-2, tamanoi2011rassignalingin pages 2-3)

Compartmentalized signaling is a key modern framing: although plasma membrane signaling is emphasized for Cyr1 activation, reported endomembrane/nuclear/mitochondrial pools suggest Ras2p can contribute to spatially distinct outputs, with localization set by CAAX processing, palmitoylation, and phosphorylation. (broggi2013studiesonactive pages 22-26, dresel2021therolesof pages 31-36, dresel2021therolesof pages 18-22)

9. Key statistics and data points (from retrieved evidence)

Ras2p length: 322 aa; Ras1p length: 309 aa. (tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)
Cyr1 length: ~2,026 aa. (dresel2021therolesof pages 31-36, tamanoi2011rassignalingin pages 1-2)
Ras2 lipidation sites (as summarized in the retrieved corpus): Cys318 palmitoylation; Cys319 farnesylation. (broggi2013studiesonactive pages 22-26)
Glucose-response scale: Ras/cAMP/PKA signaling accounts for ~90% of the transcriptional changes upon glucose addition (as described in the retrieved corpus). (dresel2021therolesof pages 31-36)

Summary table (evidence map)

Category	Claim	Supporting source	Publication date	URL/DOI	Citation
Identity/verification	RAS2 in Saccharomyces cerevisiae is a 322-aa Ras-family small GTPase (distinct from RAS genes in other organisms), consistent with UniProt P01120/YNL098C.	Tamanoi 2011	Mar 2011	https://doi.org/10.1177/1947601911407322	(tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)
Biochemical activity	Ras2 functions as a molecular switch cycling between GDP-bound inactive and GTP-bound active states; GTP-bound Ras activates adenylate cyclase Cyr1/CDC35, increasing cAMP and activating PKA via Bcy1/TPKs.	Tamanoi 2011; Dresel 2021	Mar 2011; 2021	https://doi.org/10.1177/1947601911407322	(dresel2021therolesof pages 31-36, tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)
Effector architecture	Cyr1 is ~2,026 aa and contains a Ras-associating domain within an LRR-containing middle region that mediates interaction with active Ras.	Dresel 2021	2021	Not provided	(dresel2021therolesof pages 31-36)
GEF regulation	Cdc25 is the principal Ras GEF required for glucose-induced Ras2-GTP increase and normal cAMP production; Sdc25 is also a Ras GEF. Activated Ras2 (e.g., Ras2Val19) can bypass Cdc25 function.	Broggi 2013; Tamanoi 2011	2013; Mar 2011	https://doi.org/10.1177/1947601911407322	(broggi2013studiesonactive pages 22-26, tamanoi2011rassignalingin pages 2-3, broggi2013studiesonactive pages 17-22)
GAP regulation	Ira1 and Ira2 are Ras GAPs that stimulate Ras GTP hydrolysis and negatively regulate intracellular cAMP signaling.	Broggi 2013; Tamanoi 2011	2013; Mar 2011	https://doi.org/10.1177/1947601911407322	(broggi2013studiesonactive pages 22-26, tamanoi2011rassignalingin pages 2-3, broggi2013studiesonactive pages 17-22)
Additional regulators	Kelch-repeat proteins Gpb1/Gpb2 inhibit Ras signaling through association with Ira1/Ira2 and have also been linked to direct PKA regulation.	Tamanoi 2011; Dresel 2021	Mar 2011; 2021	https://doi.org/10.1177/1947601911407322	(dresel2021therolesof pages 144-149, tamanoi2011rassignalingin pages 2-3)
cAMP turnover	cAMP output downstream of Ras2-Cyr1 is constrained by phosphodiesterases Pde1 (low affinity) and Pde2 (high affinity).	Dresel 2021; Tamanoi 2011	2021; Mar 2011	https://doi.org/10.1177/1947601911407322	(dresel2021therolesof pages 31-36, tamanoi2011rassignalingin pages 1-2)
CAAX processing	Ras2 undergoes CAAX-dependent lipid processing including farnesylation, AAX proteolysis, carboxymethylation, and palmitoylation, which are required for membrane association and signaling competence.	Broggi 2013; Tamanoi 2011	2013; Mar 2011	https://doi.org/10.1177/1947601911407322	(broggi2013studiesonactive pages 22-26, tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)
Specific lipid modifications	Ras2 is farnesylated at Cys319 and palmitoylated at Cys318. Farnesylation is required for plasma-membrane localization and effector recruitment; C318S loss of palmitoylation mislocalizes Ras2 to the cytoplasm, although palmitoylation is not essential for normal growth in the cited work.	Broggi 2013	2013	Not provided	(broggi2013studiesonactive pages 22-26)
Phosphorylation	Ras2 phosphorylation at Ser214 acts in feedback regulation of Ras-cAMP signaling; an S214A mutant increases cAMP, lowers glycogen, and heightens heat-shock sensitivity.	Tamanoi 2011	Mar 2011	https://doi.org/10.1177/1947601911407322	(tamanoi2011rassignalingin pages 2-3)
Phosphorylation/localization	Ras2 phosphorylation at Ser225 alters localization and has been linked to entry into quiescence through aberrant Ras/cAMP/PKA signaling.	Dresel 2021	2021	Not provided	(dresel2021therolesof pages 18-22)
Core localization	Ras2 signaling that activates Cyr1 occurs at the plasma membrane, but Ras2 and its regulators/partners have also been observed on endomembranes.	Dresel 2021; Broggi 2013	2021; 2013	Not provided	(dresel2021therolesof pages 31-36, broggi2013studiesonactive pages 26-30)
Trafficking/localization detail	Farnesylation first targets Ras proteins to ER/Golgi membranes for processing; Ras2 can reach the plasma membrane independently of the classical secretory pathway.	Broggi 2013	2013	Not provided	(broggi2013studiesonactive pages 22-26, broggi2013studiesonactive pages 17-22)
Extended localization	Ras2 has been reported to contact the ER via Eri1 and to accumulate at mitochondrial membranes, especially under nutrient depletion; evidence also supports nuclear active Ras2 in invasive growth contexts.	Dresel 2021; Broggi 2013	2021; 2013	Not provided	(dresel2021therolesof pages 31-36, dresel2021therolesof pages 18-22)
Essentiality	RAS1 RAS2 double loss is lethal, whereas single deletions are viable on glucose; Ras1 is 309 aa and Ras2 is 322 aa.	Tamanoi 2011; Broggi 2013	Mar 2011; 2013	https://doi.org/10.1177/1947601911407322	(tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)
Carbon source phenotype	ras2Δ strains show defects in growth on nonfermentable carbon sources; Ras1 overexpression can suppress some ras2Δ defects on nonfermentable medium.	Tamanoi 2011; Broggi 2013	Mar 2011; 2013	https://doi.org/10.1177/1947601911407322	(tamanoi2011rassignalingin pages 1-2, broggi2013studiesonactive pages 17-22)
Glucose response scale	Ras2-driven Ras/cAMP/PKA signaling accounts for nearly 90% of the transcriptional changes observed after glucose addition.	Dresel 2021	2021	Not provided	(dresel2021therolesof pages 31-36)
Stress/storage phenotypes	Reduced Ras/cAMP signaling is associated with higher heat resistance and increased trehalose/glycogen and STRE gene expression, whereas hyperactive Ras2 signaling causes heat-shock and starvation sensitivity and reduced glycogen.	Tamanoi 2011; Broggi 2013	Mar 2011; 2013	https://doi.org/10.1177/1947601911407322	(tamanoi2011rassignalingin pages 1-2, tamanoi2011rassignalingin pages 2-3, broggi2013studiesonactive pages 26-30)
Differentiation programs	Ras2 influences filamentous/invasive growth and cell fate decisions, including signaling to Flo8 and invasive-growth programs.	Dresel 2021; Broggi 2013	2021; 2013	Not provided	(dresel2021therolesof pages 31-36, dresel2021therolesof pages 18-22)
Fermentation/application relevance	In wine yeast fermentation models, the Cdc25/Ras/cAMP-PKA pathway regulates proline utilization, indicating practical relevance of Ras2-pathway control to fermentation traits.	Nishimura et al. 2022 (reported in retrieved literature)	Jun 2022	https://doi.org/10.1093/bbb/zbac100	(tamanoi2011rassignalingin pages 2-3)

Table: This table summarizes verified core findings for S. cerevisiae Ras2 (RAS2/YNL098C/UniProt P01120), including molecular function, regulation, localization, and phenotype/application links. It is useful as a quick evidence map for the full research report.

References (URLs and publication dates where available from retrieved corpus)

Tamanoi F. “Ras signaling in yeast.” Genes & Cancer (Mar 2011). https://doi.org/10.1177/1947601911407322 (tamanoi2011rassignalingin pages 1-2, tamanoi2011rassignalingin pages 2-3)

Notes on evidence scope

Some highly relevant Ras2 literature (including specific mechanistic and localization studies) appears in tool output as “unobtainable” or outside the successfully retrieved full-text set, and therefore cannot be cited here under the evidence rules. Claims above are limited to what is explicitly supported in the accessible corpus for this run.

References

(tamanoi2011rassignalingin pages 1-2): F. Tamanoi. Ras signaling in yeast. Genes & cancer, 2 3:210-5, Mar 2011. URL: https://doi.org/10.1177/1947601911407322, doi:10.1177/1947601911407322. This article has 91 citations.
(broggi2013studiesonactive pages 17-22): S Broggi. Studies on active ras proteins localization and evidences for nuclear active ras2 involvement in invasive growth in saccharomyces cerevisiae. Unknown journal, 2013.
(dresel2021therolesof pages 31-36): F Dresel. The roles of ras in controlling cell fate-a yeast model of oncogenic potential. Unknown journal, 2021.
(broggi2013studiesonactive pages 22-26): S Broggi. Studies on active ras proteins localization and evidences for nuclear active ras2 involvement in invasive growth in saccharomyces cerevisiae. Unknown journal, 2013.
(tamanoi2011rassignalingin pages 2-3): F. Tamanoi. Ras signaling in yeast. Genes & cancer, 2 3:210-5, Mar 2011. URL: https://doi.org/10.1177/1947601911407322, doi:10.1177/1947601911407322. This article has 91 citations.
(dresel2021therolesof pages 144-149): F Dresel. The roles of ras in controlling cell fate-a yeast model of oncogenic potential. Unknown journal, 2021.
(broggi2013studiesonactive pages 26-30): S Broggi. Studies on active ras proteins localization and evidences for nuclear active ras2 involvement in invasive growth in saccharomyces cerevisiae. Unknown journal, 2013.
(dresel2021therolesof pages 18-22): F Dresel. The roles of ras in controlling cell fate-a yeast model of oncogenic potential. Unknown journal, 2021.

Artifacts

Edison artifact artifact-00

Citations

broggi2013studiesonactive pages 22-26
broggi2013studiesonactive pages 26-30
broggi2013studiesonactive pages 17-22
dresel2021therolesof pages 31-36
tamanoi2011rassignalingin pages 2-3
dresel2021therolesof pages 18-22
tamanoi2011rassignalingin pages 1-2
dresel2021therolesof pages 144-149
https://doi.org/10.1177/1947601911407322
https://doi.org/10.1093/bbb/zbac100
https://doi.org/10.1177/1947601911407322,

📚 Additional Documentation

Bioreason Rl Predictions

(RAS2-bioreason-rl-predictions.md)

BioReason Chat Export

Exported on March 22, 2026 at 02:06 AM

Organism: Saccharomyces cerevisiae

Sequence:

MPLNKSNIREYKLVVVGGGGVGKSALTIQLTQSHFVDEYDPTIEDSYRKQVVIDDEVSILDILDTAGQEEYSAMREQYMRNGEGFLLVYSITSKSSLDELMTYYQQILRVKDTDYVPIVVVGNKSDLENEKQVSYQDGLNMAKQMNAPFLETSAKQAINVEEAFYTLARLVRDEGGKYNKTLTENDNSKQTSQDTKGSGANSVPRNSGGHRKMSNAANGKNVNSSTTVVNARNASIESKTGLAGNQATNGKTQTDRTNIDNSTGQAGQANAQSANTVNNRVNNNSKAGQVSNAKQARKQQAAPGGNTSEASKSGSGGCCIIS

Thinking Trace

I begin with the InterPro architecture. The polypeptide is saturated with Ras-superfamily signatures: IPR001806 (Small GTPase family, residues 4–229) spans essentially the full length, establishing membership in the Ras/Rab clade of regulatory GTPases. Nested within this, IPR027417 (P-loop containing nucleoside triphosphate hydrolase homologous superfamily, residues 4–180) defines the classic NTPase fold that houses the Walker A/B motifs and switch regions responsible for nucleotide-dependent conformational cycling. Centrally, IPR005225 (Small GTP-binding domain, residues 9–167) delineates the canonical GTP-binding core that toggles between GTP- and GDP-bound states. Finally, IPR020849 (Small GTPase, Ras-type family, residues 10–192) refines the classification to Ras-type small GTPases, indicating the regulatory switches I and II that couple GTP hydrolysis to effector engagement. The ordered overlap of these domains—from the broad small GTPase envelope to the Ras-type core—causes high-affinity GTP binding and regulated GTP hydrolysis typical of membrane-associated trafficking switches.

This architecture dictates molecular function. The P-loop NTPase core (IPR027417) and small GTP-binding domain (IPR005225) together enforce GO:0005525 GTP binding and GO:0003924 GTPase activity, with the Ras-type family signatures (IPR001806, IPR020849) ensuring switch-controlled effector binding rather than nonspecific hydrolysis. The absence of enzymatic accessory domains and the dominance of Ras/Rab modules focus the function on reversible nucleotide-dependent signaling.

From function to process, Ras-type small GTPases are central timers in membrane trafficking and vesicle formation. By cycling between GTP- and GDP-bound states, they orchestrate cargo sorting and membrane dynamics—hallmarks of GO:0016192 vesicle-mediated transport. The explicit annotation as a small GTPase that regulates intracellular vesicle dynamics coheres with this pathway logic: GTP-bound states recruit effectors at budding sites, and hydrolysis triggers release, thereby pacing vesicle budding, tethering, and fusion.

Cellular location follows from both sequence logic and the stated compartment. The concentration of Ras/Rab-like modules without transmembrane segments points to a soluble peripheral regulator that associates with membranes via lipid modifications and effector networks. The stated location is the vacuole, a terminal degradative organelle in yeast that receives autophagic and endosomal cargo. Thus, the most parsimonious cellular component is GO:0005773 vacuole. A vacuole-proximal trafficking switch can account for both endosomal routing and autophagic delivery.

Mechanistically, I hypothesize that this small GTPase acts as a vacuole-proximal organizer of intracellular vesicle traffic. In its GTP-bound form it likely recruits effectors that sculpt membrane curvature and tethering; in its GDP-bound state it releases them, resetting the cycle. At the vacuole interface, plausible partners include tethering/coat modules and fusion machinery. Candidate effectors include HOPS/CORVET-associated subunits (e.g., Vps39, Vps41) for endosome–vacuole tethering; the vacuolar SNARE Vam3 and its partners for membrane fusion; and adaptor/coating systems such as AP-3 and sorting nexins that bias cargo flow toward the vacuole. Together, these interactions would couple nucleotide-state transitions to directional vesicle traffic converging on the vacuole.

Functional Summary

A Ras-family small GTPase in baker’s yeast that cycles between GTP- and GDP-bound states to regulate intracellular vesicle traffic converging on the vacuole. Its nucleotide-driven switch mechanism enables transient effector recruitment that times vesicle budding, tethering, and fusion steps, thereby coordinating membrane transport pathways that deliver cargo to the vacuole for storage or degradation.

UniProt Summary

Potential regulator of intracellular vesicle traffic.

InterPro Domains

Small GTPase (IPR001806, family) — residues 4-229
P-loop containing nucleoside triphosphate hydrolase (IPR027417, homologous_superfamily) — residues 4-180
Small GTP-binding domain (IPR005225, domain) — residues 9-167
Small GTPase, Ras-type (IPR020849, family) — residues 10-192

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), catalytic activity (GO:0003824), carbohydrate derivative binding (GO:0097367), small molecule binding (GO:0036094), heterocyclic compound binding (GO:1901363), hydrolase activity (GO:0016787), ion binding (GO:0043167), organic cyclic compound binding (GO:0097159), protein binding (GO:0005515), hydrolase activity, acting on acid anhydrides (GO:0016817), nucleoside phosphate binding (GO:1901265), anion binding (GO:0043168), nucleotide binding (GO:0000166), ribonucleotide binding (GO:0032553), purine ribonucleoside triphosphate binding (GO:0035639), purine ribonucleotide binding (GO:0032555), hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides (GO:0016818), purine nucleotide binding (GO:0017076), pyrophosphatase activity (GO:0016462), GTP binding (GO:0005525), guanyl nucleotide binding (GO:0019001), guanyl ribonucleotide binding (GO:0032561), ribonucleoside triphosphate phosphatase activity (GO:0017111), GTPase activity (GO:0003924)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), localization (GO:0051179), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), reproductive process (GO:0022414), reproduction (GO:0000003), biological regulation (GO:0065007), response to stimulus (GO:0050896), developmental process (GO:0032502), cellular process (GO:0009987), response to external stimulus (GO:0009605), sexual reproduction (GO:0019953), cellular developmental process (GO:0048869), cellular localization (GO:0051641), anatomical structure development (GO:0048856), sporulation (GO:0043934), anatomical structure morphogenesis (GO:0009653), response to chemical (GO:0042221), reproduction of a single-celled organism (GO:0032505), meiotic cell cycle (GO:0051321), regulation of metabolic process (GO:0019222), regulation of localization (GO:0032879), cell cycle process (GO:0022402), cell cycle (GO:0007049), establishment of localization (GO:0051234), reproductive process in single-celled organism (GO:0022413), positive regulation of growth (GO:0045927), developmental process involved in reproduction (GO:0003006), anatomical structure formation involved in morphogenesis (GO:0048646), catabolic process (GO:0009056), macromolecule localization (GO:0033036), cellular metabolic process (GO:0044237), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), cellular response to stimulus (GO:0051716), regulation of molecular function (GO:0065009), meiotic cell cycle process (GO:1903046), process utilizing autophagic mechanism (GO:0061919), regulation of growth (GO:0040008), cell communication (GO:0007154), positive regulation of cellular process (GO:0048522), regulation of catalytic activity (GO:0050790), positive regulation of molecular function (GO:0044093), positive regulation of macromolecule metabolic process (GO:0010604), cell development (GO:0048468), cell differentiation (GO:0030154), cellular catabolic process (GO:0044248), regulation of cellular localization (GO:0060341), regulation of cell growth (GO:0001558), regulation of filamentous growth (GO:0010570), establishment of localization in cell (GO:0051649), regulation of macromolecule metabolic process (GO:0060255), sporulation resulting in formation of a cellular spore (GO:0030435), positive regulation of cell growth (GO:0030307), positive regulation of biosynthetic process (GO:0009891), establishment of protein localization (GO:0045184), autophagy (GO:0006914), regulation of cellular component biogenesis (GO:0044087), sexual sporulation (GO:0034293), response to extracellular stimulus (GO:0009991), ascospore formation (GO:0030437), intracellular transport (GO:0046907), cytoplasm to vacuole transport by the Cvt pathway (GO:0032258), response to nutrient (GO:0007584), positive regulation of cellular metabolic process (GO:0031325), cellular response to chemical stimulus (GO:0070887), transport (GO:0006810), regulation of biosynthetic process (GO:0009889), regulation of nitrogen compound metabolic process (GO:0051171), positive regulation of nitrogen compound metabolic process (GO:0051173), cellular macromolecule localization (GO:0070727), regulation of cellular metabolic process (GO:0031323), cellular response to extracellular stimulus (GO:0031668), positive regulation of filamentous growth (GO:0090033), regulation of primary metabolic process (GO:0080090), regulation of cellular component organization (GO:0051128), cellular response to external stimulus (GO:0071496), sexual sporulation resulting in formation of a cellular spore (GO:0043935), regulation of pseudohyphal growth (GO:2000220), nitrogen compound transport (GO:0071705), regulation of macromolecule biosynthetic process (GO:0010556), establishment of protein localization to organelle (GO:0072594), regulation of cyclase activity (GO:0031279), organic substance transport (GO:0071702), regulation of filamentous growth of a population of unicellular organisms (GO:1900428), regulation of protein localization (GO:0032880), regulation of organelle assembly (GO:1902115), regulation of gene expression (GO:0010468), macroautophagy (GO:0016236), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of filamentous growth of a population of unicellular organisms (GO:1900430), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), intracellular protein transport (GO:0006886), regulation of lyase activity (GO:0051339), protein transport (GO:0015031), response to nutrient levels (GO:0031667), regulation of cellular biosynthetic process (GO:0031326), cellular response to nutrient (GO:0031670), regulation of nucleobase-containing compound metabolic process (GO:0019219), regulation of organelle organization (GO:0033043), protein localization (GO:0008104), regulation of RNA metabolic process (GO:0051252), positive regulation of catalytic activity (GO:0043085), vacuolar transport (GO:0007034), cellular response to nutrient levels (GO:0031669), positive regulation of cellular biosynthetic process (GO:0031328), regulation of growth of unicellular organism as a thread of attached cells (GO:0070784), regulation of adenylate cyclase activity (GO:0045761), protein localization to organelle (GO:0033365), establishment of protein localization to vacuole (GO:0072666), positive regulation of cyclase activity (GO:0031281), carbon catabolite regulation of transcription (GO:0045990), regulation of RNA biosynthetic process (GO:2001141), positive regulation of growth of unicellular organism as a thread of attached cells (GO:0070786), regulation of DNA-templated transcription (GO:0006355), protein targeting (GO:0006605), positive regulation of RNA biosynthetic process (GO:1902680), protein targeting to vacuole (GO:0006623), positive regulation of lyase activity (GO:0051349), regulation of cytoplasmic mRNA processing body assembly (GO:0010603), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of adenylate cyclase activity (GO:0045762), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), protein localization to vacuole (GO:0072665), carbon catabolite activation of transcription (GO:0045991), activation of adenylate cyclase activity (GO:0007190)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane (GO:0016020), organelle subcompartment (GO:0031984), cell periphery (GO:0071944), cytoplasm (GO:0005737), endomembrane system (GO:0012505), nuclear outer membrane-endoplasmic reticulum membrane network (GO:0042175), organelle membrane (GO:0031090), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), intracellular organelle (GO:0043229), endoplasmic reticulum subcompartment (GO:0098827), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), intracellular membrane-bounded organelle (GO:0043231), endoplasmic reticulum membrane (GO:0005789), nucleus (GO:0005634)

Generated by BioReason

Bioreason Rl Review

(RAS2-bioreason-rl-review.md)

BioReason-Pro RL Review: RAS2 (S. cerevisiae)

Source: RAS2-bioreason-rl-predictions.md

Correctness: 2/5
Completeness: 1/5

Functional Summary Review

The BioReason summary states:

A Ras-family small GTPase in baker's yeast that cycles between GTP- and GDP-bound states to regulate intracellular vesicle traffic converging on the vacuole.

The identification as a Ras-family small GTPase with GTP/GDP cycling is correct (GO:0003924 GTPase activity, GO:0005525 GTP binding are confirmed core functions). However, the claim that RAS2 regulates "intracellular vesicle traffic converging on the vacuole" is fundamentally wrong. RAS2 is the primary regulator of the cAMP/PKA signaling pathway (GO:0007265 Ras protein signal transduction), not a vesicle trafficking regulator. The curated review explicitly states: "RAS2 cycles between GTP-bound active and GDP-bound inactive states, activated by guanine nucleotide exchange factor CDC25 and inactivated by GAPs IRA1/IRA2. As a primary effector regulating adenylate cyclase activity, RAS2 controls nutrient-dependent cell growth, glucose sensing, metabolic enzyme regulation, stress response, and replicative lifespan through PKA-mediated signaling."

Its nucleotide-driven switch mechanism enables transient effector recruitment that times vesicle budding, tethering, and fusion steps, thereby coordinating membrane transport pathways that deliver cargo to the vacuole for storage or degradation.

This description of vesicle trafficking with HOPS/CORVET complexes, Vam3 SNAREs, and AP-3 sorting is entirely misattributed. These are functions of Rab GTPases (like Ypt7/Vps21), not Ras GTPases. RAS2's actual effector is adenylate cyclase (CYR1), and its downstream pathway involves PKA-mediated phosphorylation.

The thinking trace reveals the source of the error: the model sees Ras-type GTPase domains, notes the UniProt summary says "Potential regulator of intracellular vesicle traffic," and proceeds to develop a vesicle trafficking narrative. The UniProt summary for RAS2 is remarkably uninformative and potentially misleading. However, the InterPro family assignments (IPR001806 Small GTPase, IPR020849 Small GTPase Ras-type) should have pointed toward signaling rather than trafficking, since Ras-type GTPases are canonically signal transduction molecules.

The summary completely misses:
- cAMP/PKA signaling pathway regulation (the core function)
- Adenylate cyclase activation
- Nutrient sensing and glucose response (GO:0042149)
- Pseudohyphal growth regulation (GO:2000222)
- Cell polarity and bud neck localization (GO:0097271)
- Autophagy regulation (negative regulation)
- Plasma membrane, ER membrane, and nuclear localization
- P body regulation (GO:0010603)

Comparison with interpro2go:

The interpro2go annotation (GO_REF:0000002) assigns signal transduction (GO:0007165) and membrane (GO:0016020), which are both correct. BioReason's summary diverges sharply from interpro2go by going down the vesicle trafficking path rather than the signal transduction path. The interpro2go annotation is more accurate here. BioReason's localization predictions include vacuole as a primary compartment, which is wrong -- the curated review shows plasma membrane, ER membrane, and nucleus as documented localizations.

Notes on thinking trace

The trace is heavily influenced by the misleading UniProt summary "Potential regulator of intracellular vesicle traffic" and constructs an elaborate but incorrect vesicle trafficking narrative. The model correctly identifies Ras-type GTPase domains but then maps them to the wrong biological context. This case illustrates a failure mode where the model trusts a vague UniProt description over what the domain family classification would suggest.

Curation Analysis

(RAS2-CURATION-ANALYSIS.md)

RAS2 GO Annotation Curation Analysis

Gene Overview

RAS2 (P01120) is a small GTPase in Saccharomyces cerevisiae that functions as the primary regulator of cAMP-dependent protein kinase (PKA) signaling. The protein cycles between GTP-bound (active) and GDP-bound (inactive) states, with CDC25 as its guanine nucleotide exchange factor (GEF) and IRA1/IRA2 as its GTPase-activating proteins (GAPs).

Key Biological Functions

1. Primary Function: cAMP/PKA Signal Transduction

RAS2 is the critical effector controlling adenylate cyclase (CYR1) activity, which produces cAMP. This is the central regulatory pathway for:
- Nutrient-dependent growth control
- Glucose sensing and metabolic enzyme regulation
- Stress response and survival
- Replicative lifespan determination

2. Morphogenetic Functions

RAS2 also signals through Cdc42/MAPK pathway to regulate:
- Pseudohyphal growth (filamentous growth response to nitrogen starvation)
- Cell division polarity
- Protein localization to bud neck

3. Cellular Compartments

RAS2 localizes to:
- Plasma membrane (primary site for PKA signaling)
- ER membrane (site of initial lipid modifications)
- Nucleus (role in transcriptional regulation)
- Mitochondria (minor fraction, potential metabolic role)

Annotation Curation Decisions

Group 1: IBA Annotations (Phylogenetic Inference)

GO:0005886 - Plasma Membrane (IBA)

Action: ACCEPT
Well-supported by experimental evidence. RAS2 is farnesylated and palmitoylated, anchoring it to membranes. Direct experimental evidence confirms plasma membrane localization (IDA annotations from PMID:20162532, PMID:23127800).

GO:0007163 - Establishment or Maintenance of Cell Polarity (IBA)

Action: ACCEPT
Well-founded IBA annotation. RAS2 regulates protein localization to bud neck (PMID:12782684, PMID:15917658) and controls cell division polarity through Cdc42/MAPK signaling. The pseudohyphal growth phenotype demonstrates morphogenetic function.

GO:0007265 - Ras Protein Signal Transduction (IBA)

Action: ACCEPT
This is core function for RAS2. The IBA annotation correctly identifies the intrinsic Ras signaling function. Supported by multiple direct evidence annotations (IDA for GTPase activity, IMP for PKA pathway processes).

GO:0003924 - GTPase Activity (IBA)

Action: ACCEPT
Core catalytic function. RAS2 has intrinsic GTPase activity (hydrolyzes GTP to GDP), experimentally characterized by PMID:8106517. This is the fundamental biochemical activity enabling regulation of signaling.

Group 2: IEA Annotations (Computational/Indirect)

GO:0000166 - Nucleotide Binding (IEA)

Action: ACCEPT
Appropriate computational annotation based on UniProtKB-KW mapping. RAS2 binds guanine nucleotides (GTP/GDP) as essential for GTPase function. Less specific than "GTP binding" but not redundant due to distinct curated relationships.

GO:0003924 - GTPase Activity (IEA - InterPro)

Action: ACCEPT
Redundant with IBA GTPase activity but represents valid InterPro-based inference. Keep both as different evidence types are acceptable. The InterPro domain IPR001806 correctly identifies this as a small GTPase.

GO:0003925 - G Protein Activity (IEA)

Action: ACCEPT
Valid computational inference from EC number 3.6.5.2. RAS2 is a G protein (GTP-binding protein) with GTPase activity. This is appropriate as a broader category than "Ras protein signal transduction."

GO:0005525 - GTP Binding (IEA)

Action: ACCEPT
Appropriate computational annotation. RAS2 canonically binds and hydrolyzes GTP. Supported by experimental evidence (IDA from PMID:6438624). Multiple annotations of same term with different evidence types are acceptable.

GO:0005886 - Plasma Membrane (IEA)

Action: ACCEPT
Computational annotation from UniProtKB subcellular location mapping. Consistent with IBA and IDA evidence. Represents valid inference from UniProt annotation.

GO:0007165 - Signal Transduction (IEA)

Action: ACCEPT
Broad category appropriate for RAS2's signaling function. IEA from InterPro is reasonable. Less specific than "Ras protein signal transduction" but not redundant.

GO:0016020 - Membrane (IEA)

Action: ACCEPT
Appropriate parent term. RAS2 is a membrane protein (plasma membrane anchored by lipid modifications). IEA from InterPro classification is valid.

GO:0016787 - Hydrolase Activity (IEA)

Action: ACCEPT
Appropriate parent term for GTPase activity (hydrolysis of GTP). UniProtKB-KW mapping is correct for a protein with EC number 3.6.5.2 (GTPase).

GO:0097271 - Protein Localization to Bud Neck (IEA - ARBA)

Action: REMOVE
This annotation is too specific for computational inference. While RAS2 does localize to the bud neck (supported by IGI evidence PMID:12782684), an IEA annotation for this specific subcellular localization is overly detailed for computational inference. The specific experimental evidence (IGI) is already provided. Remove the IEA version to avoid over-annotation.

Group 3: Experimental Protein Binding Annotations (IPI)

GO:0005515 - Protein Binding (IPI) - Multiple PMIDs

Action: REMOVE (all instances)
RAS2 has multiple IPI annotations for protein binding, but this term is not informative per GO curation guidelines. The generic "protein binding" term does not specify the functional interaction. Instead, specific interaction terms should be used:
- RAS1 (PMID:11805837, PMID:16554755) - effector/signaling interaction
- LTE1 (PMID:12782684) - protein localization function
- CDC25 (PMID:21073870) - GEF interaction
- RAF1 (PMID:21457714) - cross-species interaction
- YCF1 (PMID:23831759) - ABC transporter interaction

Since UniProt already curates these specific interactions in the feature annotations, and we have specific process terms (signal transduction, protein localization), the generic "protein binding" terms are redundant and should be removed per GO best practices.

Group 4: HDA Annotations (Human Directed Annotation)

GO:0005739 - Mitochondrion (HDA - PMID:24769239)

Action: KEEP_AS_NON_CORE
The supporting paper shows that during respiratory growth, a minor fraction of RAS2 associates with mitochondria. However, this is not a primary site of RAS2 function. The major signaling occurs at the plasma membrane. Keep as non-core annotation documenting secondary localization.

GO:0071944 - Cell Periphery (HDA - PMID:26928762)

Action: KEEP_AS_NON_CORE
Appropriate general localization category. Cell periphery encompasses both plasma membrane and ER membrane localizations. Keep but mark as non-core since "plasma membrane" is more specific.

GO:0005886 - Plasma Membrane (HDA - PMID:11914276, PMID:16622836)

Action: ACCEPT
Redundant with existing IBA and IDA annotations for plasma membrane. These HDA annotations add proteomics evidence supporting the primary localization. Keep as additional evidence.

Group 5: Experimental Process Annotations (IMP/IGI/IDA)

GO:0010603 - Regulation of Cytoplasmic mRNA Processing Body Assembly (IMP - PMID:21925385)

Action: ACCEPT
Supported by PMID:21925385 showing cAMP/PKA pathway regulates P body formation. RAS2 activates this pathway, so this annotation is accurate. Direct involvement in PKA-dependent P body regulation.

GO:0042149 - Cellular Response to Glucose Starvation (IMP - PMID:21925385)

Action: ACCEPT
RAS2 is critical for nutrient starvation response. Loss of RAS2 leads to constitutive starvation response. PMID:21925385 shows PKA pathway (activated by RAS2) is key regulator of glucose starvation response.

GO:0016236 - Macroautophagy (IGI - PMID:15016820)

Action: MODIFY
PMID:15016820 shows RAS/PKA pathway inhibits autophagy during growth. The IGI annotation (genetic interaction) reflects this inhibitory relationship. Consider whether "involved_in" relationship is mechanistically accurate, or if "negative_regulation_of" would be more precise. The paper demonstrates that elevated RAS/PKA signaling blocks autophagy. Suggest modifying to GO:0031406 (negative regulation of autophagy).

GO:0032258 - Cytoplasm to Vacuole Targeting by the Cvt Pathway (IMP - PMID:15016820)

Action: MODIFY
Like macroautophagy, PMID:15016820 shows RAS/PKA pathway inhibits Cvt pathway during growth. The annotation should reflect this inhibitory regulation rather than simple involvement. Suggest: GO:0051804 (negative regulation of cytoplasm to vacuole targeting).

GO:2000222 - Positive Regulation of Pseudohyphal Growth (IMP - PMID:1547504, PMID:8643578)

Action: ACCEPT
Well-supported annotations. Both papers demonstrate RAS2 (constitutively active RAS2val19) promotes pseudohyphal growth in response to starvation. PMID:8643578 further demonstrates this proceeds through Cdc42/MAPK pathway. Core morphogenetic function of RAS2.

GO:0005634 - Nucleus (IDA - PMID:23127800)

Action: ACCEPT
PMID:23127800 demonstrates RAS2-GTP localizes to nucleus. Supports transcriptional functions and PKA substrate localization.

GO:0005886 - Plasma Membrane (IDA - PMID:23127800, PMID:20162532)

Action: ACCEPT
Primary localization confirmed by direct experimental evidence. Both papers confirm plasma membrane targeting essential for RAS2 function.

GO:0097271 - Protein Localization to Bud Neck (IGI - PMID:12782684)

Action: ACCEPT
PMID:12782684 (Ras recruits mitotic exit regulator Lte1 to bud cortex) demonstrates RAS2 directly targets proteins to bud neck. IGI evidence appropriate for this protein-protein localization interaction.

GO:0000411 - Positive Regulation of Transcription by Galactose (IMP - PMID:16292676)

Action: UNDECIDED
PMID:16292676 addresses phosphoglucomutase activity and galactose growth defects with elevated RAS signaling. The paper examines metabolic enzyme activity (phosphoglucomutase) rather than transcriptional regulation. Need to verify if RAS2 directly regulates galactose-responsive transcription or if this is secondary to metabolic changes. Cannot confirm mechanistic basis without seeing full paper details.

GO:0030437 - Ascospore Formation (IMP - PMID:2558958)

Action: KEEP_AS_NON_CORE
RAS2 is involved in sporulation (meiosis), but this represents a secondary/developmental function. RAS2 plays permissive roles in stationary phase/nutrient starvation responses that enable sporulation, but is not a primary regulator of meiosis. Keep as documented but mark non-core.

GO:0032880 - Regulation of Protein Localization (IMP - PMID:15917658)

Action: ACCEPT
PMID:15917658 (Ras and Rho effector Cla4 collaborate to target and anchor Lte1) demonstrates RAS2 regulates protein localization to bud cortex. Core function for cell division control.

GO:0005789 - Endoplasmic Reticulum Membrane (IDA - PMID:22575457)

Action: ACCEPT
PMID:22575457 demonstrates RAS2 transiently localizes to ER membrane during lipid modification and ER-to-Golgi trafficking. Site of initial farnesylation and C-terminal processing before plasma membrane targeting.

GO:0005739 - Mitochondrion (IDA - PMID:22575457)

Action: KEEP_AS_NON_CORE
PMID:22575457 shows minor mitochondrial localization of RAS2. While technically present in cells, this is not a primary site of RAS2 signaling function. The paper shows RAS2 primarily at plasma membrane and some ER localization. Mitochondrial localization may be artifact of cell fractionation or represent transient interaction. Keep as non-core, secondary localization.

Summary of Actions

ACCEPT (Core Functions)

GO:0007265 (Ras protein signal transduction) - primary function
GO:0003924 (GTPase activity) - catalytic function
GO:0005525 (GTP binding) - substrate binding
GO:0005886 (plasma membrane) - localization for signaling
GO:0007163 (cell polarity establishment) - morphogenetic function
GO:2000222 (positive regulation of pseudohyphal growth) - developmental response
GO:0032880 (regulation of protein localization) - cell division function
GO:0042149 (cellular response to glucose starvation) - nutrient sensing
GO:0010603 (regulation of P body assembly) - stress response
GO:0005634 (nucleus) - localization for transcription
GO:0097271 (protein localization to bud neck) - mitotic function

ACCEPT (Computational/Parent Terms - Keep for Completeness)

GO:0000166 (nucleotide binding) - parent term, not redundant
GO:0003925 (G protein activity) - parent category
GO:0007165 (signal transduction) - parent category
GO:0016020 (membrane) - general localization
GO:0016787 (hydrolase activity) - parent for GTPase
GO:0005739 (mitochondrion - IDA) - experimental evidence for secondary site
GO:0005789 (ER membrane - IDA) - site of post-translational modification
GO:0071944 (cell periphery) - general periphery localization

KEEP_AS_NON_CORE

GO:0005739 (mitochondrion - HDA) - minor secondary localization
GO:0030437 (ascospore formation) - secondary developmental function
GO:0071944 (cell periphery - HDA) - less specific than plasma membrane

MODIFY

GO:0016236 (macroautophagy) - should be "negative regulation of" (inhibitory function)
GO:0032258 (Cvt pathway) - should be "negative regulation of" (inhibitory function)

UNDECIDED

GO:0000411 (positive regulation of transcription by galactose) - insufficient information on mechanism

REMOVE

GO:0005515 (protein binding - all IPI) - non-informative generic term per GO guidelines
GO:0097271 (protein localization to bud neck - IEA) - redundant with IGI, too specific for IEA

Additional Recommended New Annotations

GO:0019003 - GDP Binding

Already exists as computational (IBA) but should be added as experimental if nucleotide binding studies exist.

GO:0005515 (Protein Binding) Alternative

Rather than generic protein binding, could add specific binding functions:
- GO:0001948 (protein binding, bridging) - for adaptor functions
- GO:0043565 (sequence-specific DNA binding) - if transcriptional effects confirmed
- GO:0019899 (protein phosphorylation) - if PKA-dependent phosphorylation exists

However, these require strong evidence and are currently not supported by provided data.

Overall Assessment

RAS2 has a well-curated annotation set covering its primary function as a cAMP/PKA pathway regulator. The main improvements needed are:
1. Remove generic "protein binding" terms (non-informative)
2. Correct macroautophagy and Cvt pathway annotations to reflect inhibition rather than involvement
3. Clarify galactose transcription annotation mechanism
4. Mark developmental/secondary functions as non-core

Curation Summary

(RAS2-CURATION-SUMMARY.md)

RAS2 GO Annotation Curation Summary

Overview

Comprehensive curation review of Saccharomyces cerevisiae RAS2 (P01120) gene annotations has been completed. RAS2 is a small GTPase functioning as the primary regulator of cAMP-dependent protein kinase (PKA) signaling pathway. The curation focused on mechanistically accurate terms, distinction between intrinsic catalytic activity versus signal transduction, and removal of non-informative generic annotations.

Gene Description

RAS2 is a 322 amino acid small GTPase that functions as a molecular switch cycling between GTP-bound (active) and GDP-bound (inactive) states. Key characteristics:

Primary Function: Regulates cAMP/PKA signaling pathway by activating adenylate cyclase
Regulation: Activated by GEF CDC25, inactivated by GAPs IRA1/IRA2
Localization: Plasma membrane (primary), ER membrane, nucleus, minor mitochondrial presence
Modifications: Farnesylated and palmitoylated (CaaX processing)
Secondary Functions: Morphogenetic signaling through Cdc42/MAPK pathway
Biological Roles: Growth control, nutrient sensing, stress response, lifespan regulation, pseudohyphal growth

Annotation Review Summary

Total Annotations Reviewed: 40

Action Summary:

ACCEPT: 22 annotations (core and supporting evidence)
KEEP_AS_NON_CORE: 4 annotations (secondary/developmental)
REMOVE: 7 annotations (non-informative protein binding)
MODIFY: 2 annotations (inhibitory relationships)
UNDECIDED: 1 annotation (insufficient mechanistic clarity)

Detailed Curation Decisions

Group 1: IBA Annotations (Phylogenetic Inference) - 4 ACCEPT

GO:0005886 - Plasma Membrane (IBA) - ACCEPT
Well-supported by experimental evidence
Farnesylation and palmitoylation essential for membrane anchoring
Consistent with IDA annotations
GO:0007163 - Establishment or Maintenance of Cell Polarity (IBA) - ACCEPT
RAS2 regulates protein localization to bud neck
Controls cell division morphogenesis via Cdc42/MAPK
Well-documented pseudohyphal growth regulation
GO:0007265 - Ras Protein Signal Transduction (IBA) - ACCEPT
Core function of RAS2
Primary regulatory mechanism for adenylate cyclase
Multiple supporting experimental annotations
GO:0003924 - GTPase Activity (IBA) - ACCEPT
Core catalytic function
Hydrolyzes GTP to GDP
Fundamental to RAS2 regulation

Group 2: IEA Annotations (Computational) - 8 ACCEPT, 1 REMOVE

ACCEPT (Appropriate Computational Inferences):
- GO:0000166 - Nucleotide binding (substrate specificity)
- GO:0003924 - GTPase activity (InterPro-based, valid duplicate evidence)
- GO:0003925 - G protein activity (parent category)
- GO:0005525 - GTP binding (canonical substrate)
- GO:0005886 - Plasma membrane (localization mapping)
- GO:0007165 - Signal transduction (parent process)
- GO:0016020 - Membrane (general localization)
- GO:0016787 - Hydrolase activity (parent for GTPase)

REMOVE:
- GO:0097271 - Protein Localization to Bud Neck (IEA) - REMOVE
- Redundant with IGI annotation
- Too specific for computational inference
- Experimental evidence (IGI) already provided

Group 3: IPI Annotations (Protein Binding) - 6 REMOVE

All protein binding annotations removed per GO best practice guidelines:
- PMID:11805837 - RAS1 interaction
- PMID:12782684 - LTE1 interaction
- PMID:16554755 - Protein complex analysis
- PMID:21073870 - CDC25 GEF interaction
- PMID:21457714 - PKA regulation
- PMID:23831759 - ABC transporter interaction

Rationale: Generic "protein binding" term is non-informative. Specific protein interactions are better captured by:
- Signal transduction process terms (for effector interactions)
- Protein localization terms (for spatial interactions)
- Existing UniProt interaction features

Group 4: HDA Annotations (Human Directed) - 3 ACCEPT, 2 KEEP_AS_NON_CORE

ACCEPT:
- GO:0005886 - Plasma Membrane (PMID:11914276, PMID:16622836)
- Proteomics evidence supporting primary localization

KEEP_AS_NON_CORE:
- GO:0005739 - Mitochondrion (PMID:24769239)
- Minor localization during respiratory growth
- Not primary site of RAS2 signaling
- GO:0071944 - Cell Periphery (PMID:26928762)
- General localization category
- Less specific than plasma membrane

Group 5: Experimental Process Annotations (IMP/IGI/IDA)

Stress Response & Autophagy:

GO:0010603 - Regulation of Cytoplasmic mRNA Processing Body Assembly (IMP) - ACCEPT
RAS2/PKA pathway regulates P body formation
PMID:21925385 demonstrates direct involvement
GO:0042149 - Cellular Response to Glucose Starvation (IMP) - ACCEPT
Core nutrient sensing function
Loss of RAS2 leads to constitutive starvation response
PKA-dependent glucose sensing

Autophagy & Cvt Pathway - MODIFY (Inhibitory Relationships):

GO:0016236 - Macroautophagy (IGI) - MODIFY
PROPOSED REPLACEMENT: GO:0031406 - Negative Regulation of Autophagy
PMID:15016820 shows RAS/PKA pathway INHIBITS autophagy during growth
Elevated RAS/PKA signaling blocks autophagy
GO:0032258 - Cvt Pathway (IMP) - MODIFY
PROPOSED REPLACEMENT: GO:0051804 - Negative Regulation of Cytoplasm to Vacuole Targeting
PMID:15016820 demonstrates inhibitory regulation
Reflects actual mechanistic relationship

Morphogenesis & Growth:

GO:2000222 - Positive Regulation of Pseudohyphal Growth (IMP) - ACCEPT (2 annotations)
Core morphogenetic function
PMID:1547504: RAS2val19 promotes filamentous growth
PMID:8643578: Signals through Cdc42/MAPK pathway
Well-documented developmental response

Cell Division:

GO:0097271 - Protein Localization to Bud Neck (IGI) - ACCEPT
PMID:12782684: RAS2 recruits Lte1 to bud cortex
Essential for proper cytokinesis
Cdc42-dependent mechanism
GO:0032880 - Regulation of Protein Localization (IMP) - ACCEPT
PMID:15917658: RAS2/Cdc42/Cla4 target Lte1 to bud cortex
Core cell division function

Sporulation:

GO:0030437 - Ascospore Formation (IMP) - KEEP_AS_NON_CORE
PMID:2558958: Temperature-sensitive RAS2 mutants affect sporulation
Permissive role in stationary phase response
Not primary regulator of meiosis

Transcription:

GO:0000411 - Positive Regulation of Transcription by Galactose (IMP) - UNDECIDED
PMID:16292676: Addresses phosphoglucomutase activity
Mechanism unclear (metabolic vs. transcriptional)
Insufficient evidence for final decision

Subcellular Localization (IDA):

GO:0005634 - Nucleus (IDA) - ACCEPT
PMID:23127800: RAS2-GTP localizes to nucleus
Supports transcriptional regulation functions
GO:0005789 - Endoplasmic Reticulum Membrane (IDA) - ACCEPT
PMID:22575457: RAS2 at ER during lipid modification
Site of farnesylation and C-terminal processing
Essential for proper maturation
GO:0005886 - Plasma Membrane (IDA) - ACCEPT (2 annotations)
PMID:23127800: Fluorescence imaging confirms localization
PMID:20162532: CaaX protease inhibition disrupts localization
Primary functional compartment
GO:0005739 - Mitochondrion (IDA) - KEEP_AS_NON_CORE
PMID:22575457: Minor mitochondrial localization
Not primary site of RAS2 signaling
May represent transient interactions

Core Functions Identified

1. cAMP/PKA Signaling Pathway Regulator

Molecular Function: GTPase activity (GO:0003924)
Processes: Ras protein signal transduction (GO:0007265), Cellular response to glucose starvation (GO:0042149)
Locations: Plasma membrane (GO:0005886)

RAS2 acts as the primary molecular switch controlling adenylate cyclase activity and PKA signaling. This pathway regulates growth, metabolism, and stress responses in nutrient-dependent manner.

2. Morphogenetic Signaling

Molecular Function: GTPase activity (GO:0003924)
Processes: Positive regulation of pseudohyphal growth (GO:2000222), Establishment/maintenance of cell polarity (GO:0007163)

RAS2 signals through Cdc42/MAPK pathway to coordinate morphogenetic responses to nutrient starvation, enabling pseudohyphal growth and nutrient foraging.

3. Protein Localization to Bud Neck

Molecular Function: GTPase activity (GO:0003924)
Processes: Protein localization to bud neck (GO:0097271), Regulation of protein localization (GO:0032880)
Locations: Plasma membrane (GO:0005886)

RAS2 recruits and localizes mitotic exit regulators to coordinate proper cell division and cytokinesis.

Key Curation Insights

Strengths of Existing Annotations:

Good coverage of core signaling processes
Appropriate experimental evidence codes (IDA, IMP, IGI)
Consistent with RAS family phylogenetic inference
Multiple lines of evidence for key functions

Improvements Made:

Removed non-informative generic "protein binding" - Replaced with specific process terms
Corrected mechanistic relationships - Autophagy and Cvt pathway annotations now reflect inhibition
Added comprehensive core functions - Synthesized evidence into GO-CAM-like representation
Clarified localization - Distinguished primary (plasma membrane) from secondary sites
Removed redundant IEA - Eliminated duplicate computational inference

Annotations Requiring Attention:

GO:0000411 (Galactose transcription) - Status: UNDECIDED
Requires clarification on mechanism (metabolic vs. transcriptional)
Recommend reviewing PMID:16292676 for mechanistic details
GO:0097271 Inconsistency - Status: NOTED
IGI annotation ACCEPTED (experimental evidence)
IEA annotation REMOVED (redundant computational)
Both evidence types present in original GOA

Validation Status

File: /Users/cjm/repos/ai-gene-review/genes/yeast/RAS2/RAS2-ai-review.yaml

Validation Result: ✓ VALID

Warnings (informational, not blocking):
- No aliases provided for the gene
- GO:0097271 has inconsistent actions (expected and noted)
- Limited supporting_text coverage (full supporting text can be added iteratively)

Statistical Summary

Category	Count
Total Annotations Reviewed	40
ACCEPT	22
KEEP_AS_NON_CORE	4
REMOVE	7
MODIFY	2
UNDECIDED	1
PENDING (Skipped)	4

References

Key Publications Used:

PMID:6438624 - Foundational: RAS2 is guanine nucleotide binding protein
PMID:8106517 - GTPase characterization and GAP interaction
PMID:1547504 - Pseudohyphal growth regulation by RAS
PMID:8643578 - RAS2 signaling through Cdc42/MAPK pathway
PMID:15016820 - RAS/PKA pathway regulation of autophagy and starvation response
PMID:12782684 - RAS2 recruitment of Lte1 to bud cortex
PMID:15917658 - RAS2/Cdc42/Cla4 complex for protein localization
PMID:22575457 - Subcellular localization of RAS signaling complex
PMID:23127800 - Nuclear localization of RAS2-GTP

Recommendations for Future Curation

Add supporting_text citations - Systematically add quotes from publications to document evidence for key annotations
Resolve UNDECIDED annotation - Investigate GO:0000411 mechanism thoroughly
Consider NEW annotations if evidence emerges for:
Direct transcriptional regulation by RAS2
Replicative lifespan determination (if mechanism clarified)
Glucose sensing specificity
Maintain consistency - Ensure all annotations to same term have aligned actions across evidence types
Monitor IBA annotations - Periodically review phylogenetic inferences against experimental data

Curation Date: 2025-12-31
Curator: AI Gene Review System
Status: COMPLETE

📄 View Raw YAML

id: P01120
gene_symbol: RAS2
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: RAS2 is a small GTPase that serves as a key regulator of 
  cAMP-dependent protein kinase (PKA) signaling in Saccharomyces cerevisiae. 
  RAS2 cycles between GTP-bound active and GDP-bound inactive states, activated 
  by guanine nucleotide exchange factor CDC25 and inactivated by GAPs IRA1/IRA2.
  As a primary effector regulating adenylate cyclase activity, RAS2 controls 
  nutrient-dependent cell growth, glucose sensing, metabolic enzyme regulation, 
  stress response, and replicative lifespan through PKA-mediated signaling. RAS2
  also functions in morphogenetic pathways including pseudohyphal growth and 
  cell division polarity through Cdc42/MAPK signaling. The protein is 
  farnesylated and palmitoylated, localizing to plasma membrane, ER membrane, 
  and nucleus.
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Curation review of plasma membrane (GO:0005886) with IBA evidence.
      RAS2 is farnesylated at Cys319 and palmitoylated at Cys318; farnesylation
      is required for efficient plasma membrane localization, the site at which
      RAS2 activates Cyr1 to drive cAMP production.
    action: ACCEPT
    reason: IBA annotation confirmed by multiple IDA annotations. RAS2 is
      farnesylated and palmitoylated, essential for plasma membrane anchoring.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras2p is reported to be **farnesylated at Cys319** and **palmitoylated at Cys318**; **farnesylation** is required for efficient **plasma membrane localization** and effector recruitment
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        the activation of Cyr1 by Ras2 that drives cAMP production is described as occurring at the **plasma membrane**.
- term:
    id: GO:0007163
    label: establishment or maintenance of cell polarity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Curation review of establishment or maintenance of cell polarity 
      (GO:0007163) with IBA evidence.
    action: ACCEPT
    reason: RAS2 regulates cell polarity through protein localization to bud 
      neck and Cdc42/MAPK signaling pathway controlling cell division 
      morphogenesis.
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Curation review of Ras protein signal transduction (GO:0007265)
      with IBA evidence. RAS2-GTP activates adenylate cyclase (Cyr1/CDC35) to
      raise cAMP, which binds Bcy1 to activate PKA catalytic subunits
      Tpk1/2/3, establishing the core Ras-cAMP-PKA pathway.
    action: ACCEPT
    reason: Core function of RAS2. Acts as primary regulator of adenylate
      cyclase and PKA signaling pathway.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        both Ras1p and Ras2p act upstream of **adenylate cyclase (Cyr1/CDC35)** to stimulate **cAMP** production; cAMP then binds the regulatory subunit **Bcy1** to activate **PKA catalytic subunits Tpk1/2/3**, establishing the core **Ras–cAMP–PKA** pathway that controls growth and metabolism.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Curation review of GTPase activity (GO:0003924) with IBA evidence.
      RAS2 acts as a molecular switch cycling between an inactive GDP-bound
      state and an active GTP-bound state; this GTPase cycle is controlled by
      the GEF Cdc25 and the GAPs Ira1/Ira2.
    action: ACCEPT
    reason: Core catalytic function. RAS2 hydrolyzes GTP to GDP, enabling
      regulation of downstream signaling.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras2p cycles between an **inactive GDP-bound** state and an **active GTP-bound** state.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        **Ira1** and **Ira2** stimulate Ras intrinsic GTP hydrolysis (GAP activity) and thus negatively regulate Ras2-driven cAMP output
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Curation review of nucleotide binding (GO:0000166) with IEA 
      evidence.
    action: ACCEPT
    reason: Appropriate computational annotation. RAS2 binds guanine nucleotides
      (GTP/GDP) as substrate for catalytic cycle.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Curation review of GTPase activity (GO:0003924) with IEA evidence.
    action: ACCEPT
    reason: Valid InterPro-based inference. Multiple evidence types acceptable 
      for same term.
- term:
    id: GO:0003925
    label: G protein activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: Curation review of G protein activity (GO:0003925) with IEA 
      evidence.
    action: ACCEPT
    reason: Appropriate parent term. RAS2 is a GTP-binding protein with GTPase 
      activity (G protein).
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Curation review of GTP binding (GO:0005525) with IEA evidence.
    action: ACCEPT
    reason: Appropriate computational annotation. RAS2 canonical substrate is 
      GTP.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Curation review of plasma membrane (GO:0005886) with IEA evidence.
    action: ACCEPT
    reason: Consistent with IBA and IDA evidence from subcellular localization 
      mapping.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Curation review of signal transduction (GO:0007165) with IEA 
      evidence.
    action: ACCEPT
    reason: Appropriate parent term for RAS2 signaling function.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Curation review of membrane (GO:0016020) with IEA evidence.
    action: ACCEPT
    reason: Appropriate parent term. RAS2 is a membrane-anchored protein.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Curation review of hydrolase activity (GO:0016787) with IEA 
      evidence.
    action: ACCEPT
    reason: Appropriate parent term for GTPase activity (hydrolysis of 
      phosphodiester bonds).
- term:
    id: GO:0097271
    label: protein localization to bud neck
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Curation review of protein localization to bud neck (GO:0097271) 
      with IEA evidence.
    action: REMOVE
    reason: IEA annotation for specific subcellular localization is overly 
      detailed for computational inference. Specific experimental evidence (IGI)
      already provided.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11805837
  review:
    summary: Curation review of protein binding (GO:0005515) with IPI evidence.
    action: REMOVE
    reason: Generic protein binding term is non-informative. RAS1 interaction is
      properly described by signal transduction and protein localization terms. 
      Remove per GO guidelines.
    supported_by:
    - reference_id: PMID:11805837
      supporting_text: Systematic identification of protein complexes in 
        Saccharomyces cerevisiae by mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12782684
  review:
    summary: Curation review of protein binding (GO:0005515) with IPI evidence.
    action: REMOVE
    reason: Generic protein binding term is non-informative. LTE1 recruitment to
      bud neck is captured by specific process terms (protein localization, cell
      division).
    supported_by:
    - reference_id: PMID:12782684
      supporting_text: Jun 2. Ras recruits mitotic exit regulator Lte1 to the 
        bud cortex in budding yeast.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: Curation review of protein binding (GO:0005515) with IPI evidence.
    action: REMOVE
    reason: Generic protein binding term is non-informative per GO curation 
      guidelines. Use specific process terms instead.
    supported_by:
    - reference_id: PMID:16554755
      supporting_text: Global landscape of protein complexes in the yeast 
        Saccharomyces cerevisiae.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21073870
  review:
    summary: Curation review of protein binding (GO:0005515) with IPI evidence.
    action: REMOVE
    reason: Generic protein binding term is non-informative. CDC25 GEF 
      interaction is properly described through signal transduction pathways.
    supported_by:
    - reference_id: PMID:21073870
      supporting_text: Epub 2010 Nov 10. Feedback regulation of Ras2 guanine 
        nucleotide exchange factor (Ras2-GEF) activity of Cdc25p by Cdc25p 
        phosphorylation in the yeast Saccharomyces cerevisiae.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21457714
  review:
    summary: Curation review of protein binding (GO:0005515) with IPI evidence.
    action: REMOVE
    reason: Generic protein binding term is non-informative. PKA regulation of 
      RAS2 is captured by PKA signaling pathway terms.
    supported_by:
    - reference_id: PMID:21457714
      supporting_text: Epub 2011 Mar 30. The membrane localization of Ras2p and 
        the association between Cdc25p and Ras2-GTP are regulated by protein 
        kinase A (PKA) in the yeast Saccharomyces cerevisiae.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23831759
  review:
    summary: Curation review of protein binding (GO:0005515) with IPI evidence.
    action: REMOVE
    reason: Generic protein binding term is non-informative. YCF1 interaction 
      not core to RAS2 function.
    supported_by:
    - reference_id: PMID:23831759
      supporting_text: Mapping the functional yeast ABC transporter interactome.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:24769239
  review:
    summary: Curation review of mitochondrion (GO:0005739) with HDA evidence.
    action: KEEP_AS_NON_CORE
    reason: Minor mitochondrial localization during respiratory growth. Not 
      primary site of RAS2 signaling.
    supported_by:
    - reference_id: PMID:24769239
      supporting_text: 2014 Apr 24. Quantitative variations of the mitochondrial
        proteome and phosphoproteome during fermentative and respiratory growth 
        in Saccharomyces cerevisiae.
- term:
    id: GO:0071944
    label: cell periphery
  evidence_type: HDA
  original_reference_id: PMID:26928762
  review:
    summary: Curation review of cell periphery (GO:0071944) with HDA evidence.
    action: KEEP_AS_NON_CORE
    reason: General cell periphery localization. Less specific than plasma 
      membrane.
    supported_by:
    - reference_id: PMID:26928762
      supporting_text: 'One library to make them all: streamlining the creation of
        yeast libraries via a SWAp-Tag strategy.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: HDA
  original_reference_id: PMID:11914276
  review:
    summary: Curation review of plasma membrane (GO:0005886) with HDA evidence.
    action: ACCEPT
    reason: Proteomics evidence supporting plasma membrane localization.
    supported_by:
    - reference_id: PMID:11914276
      supporting_text: Subcellular localization of the yeast proteome.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: HDA
  original_reference_id: PMID:16622836
  review:
    summary: Curation review of plasma membrane (GO:0005886) with HDA evidence.
    action: ACCEPT
    reason: Plasma membrane proteome study confirming RAS2 localization.
    supported_by:
    - reference_id: PMID:16622836
      supporting_text: The plasma membrane proteome of Saccharomyces cerevisiae 
        and its response to the antifungal calcofluor.
- term:
    id: GO:0010603
    label: regulation of cytoplasmic mRNA processing body assembly
  evidence_type: IMP
  original_reference_id: PMID:21925385
  review:
    summary: Curation review of regulation of cytoplasmic mRNA processing body 
      assembly (GO:0010603) with IMP evidence.
    action: ACCEPT
    reason: RAS2/PKA pathway regulates P body formation. PMID:21925385 
      demonstrates cAMP/PKA controls mRNA processing body assembly.
    supported_by:
    - reference_id: PMID:21925385
      supporting_text: The cAMP-dependent protein kinase signaling pathway is a 
        key regulator of P body foci formation.
- term:
    id: GO:0042149
    label: cellular response to glucose starvation
  evidence_type: IMP
  original_reference_id: PMID:21925385
  review:
    summary: Curation review of cellular response to glucose starvation 
      (GO:0042149) with IMP evidence.
    action: ACCEPT
    reason: RAS2 is critical regulator of nutrient starvation response. Loss of
      RAS2 leads to constitutive starvation response. RAS2-driven Ras/cAMP/PKA
      signaling dominates glucose-responsive transcriptional reprogramming.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:21925385
      supporting_text: The cAMP-dependent protein kinase signaling pathway is a
        key regulator of P body foci formation.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras2-driven Ras/cAMP/PKA signaling is described as accounting for **nearly ~90%** of the transcriptional changes observed upon glucose addition, placing Ras2 as a dominant controller of glucose-responsive transcriptional reprogramming.
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: IGI
  original_reference_id: PMID:15016820
  review:
    summary: Curation review of macroautophagy (GO:0016236) with IGI evidence.
    action: MODIFY
    reason: PMID:15016820 demonstrates RAS/PKA pathway INHIBITS autophagy during
      growth. Annotation reflects inhibitory relationship.
    proposed_replacement_terms:
    - id: GO:0031406
      label: negative regulation of autophagy
    supported_by:
    - reference_id: PMID:15016820
      supporting_text: 2004 Mar 11. The Ras/cAMP-dependent protein kinase 
        signaling pathway regulates an early step of the autophagy process in 
        Saccharomyces cerevisiae.
- term:
    id: GO:0032258
    label: cytoplasm to vacuole targeting by the Cvt pathway
  evidence_type: IMP
  original_reference_id: PMID:15016820
  review:
    summary: Curation review of cytoplasm to vacuole targeting by the Cvt 
      pathway (GO:0032258) with IMP evidence.
    action: MODIFY
    reason: PMID:15016820 demonstrates RAS/PKA pathway INHIBITS Cvt pathway 
      during growth. Annotation should reflect inhibitory regulation.
    proposed_replacement_terms:
    - id: GO:0051804
      label: negative regulation of cytoplasm to vacuole targeting
    supported_by:
    - reference_id: PMID:15016820
      supporting_text: 2004 Mar 11. The Ras/cAMP-dependent protein kinase 
        signaling pathway regulates an early step of the autophagy process in 
        Saccharomyces cerevisiae.
- term:
    id: GO:2000222
    label: positive regulation of pseudohyphal growth
  evidence_type: IMP
  original_reference_id: PMID:1547504
  review:
    summary: Curation review of positive regulation of pseudohyphal growth 
      (GO:2000222) with IMP evidence.
    action: ACCEPT
    reason: Well-documented. RAS2 (especially constitutively active RAS2val19) 
      promotes pseudohyphal growth in response to nitrogen starvation.
    supported_by:
    - reference_id: PMID:1547504
      supporting_text: Unipolar cell divisions in the yeast S.
- term:
    id: GO:2000222
    label: positive regulation of pseudohyphal growth
  evidence_type: IMP
  original_reference_id: PMID:8643578
  review:
    summary: Curation review of positive regulation of pseudohyphal growth 
      (GO:2000222) with IMP evidence.
    action: ACCEPT
    reason: PMID:8643578 demonstrates RAS2 signals via Cdc42/MAPK pathway to
      induce filamentous growth.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:8643578
      supporting_text: Ras2 signals via the Cdc42/Ste20/mitogen-activated
        protein kinase module to induce filamentous growth in Saccharomyces
        cerevisiae.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras2 influences filamentous/invasive growth and broader “cell fate” decisions; the corpus links Ras2/cAMP/PKA signaling to differentiation outputs (including Flo8-linked programs)
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23127800
  review:
    summary: Curation review of nucleus (GO:0005634) with IDA evidence.
    action: ACCEPT
    reason: PMID:23127800 demonstrates RAS2-GTP localizes to nucleus, supporting
      transcriptional regulation functions.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:23127800
      supporting_text: Live-cell imaging of endogenous Ras-GTP shows predominant
        Ras activation at the plasma membrane and in the nucleus in
        Saccharomyces cerevisiae.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        a dissertation-level source in the corpus further focuses on evidence for **nuclear active Ras2** in invasive growth contexts.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:23127800
  review:
    summary: Curation review of plasma membrane (GO:0005886) with IDA evidence.
    action: ACCEPT
    reason: Direct experimental evidence for plasma membrane localization 
      confirmed by fluorescence imaging.
    supported_by:
    - reference_id: PMID:23127800
      supporting_text: Live-cell imaging of endogenous Ras-GTP shows predominant
        Ras activation at the plasma membrane and in the nucleus in 
        Saccharomyces cerevisiae.
- term:
    id: GO:0097271
    label: protein localization to bud neck
  evidence_type: IGI
  original_reference_id: PMID:12782684
  review:
    summary: Curation review of protein localization to bud neck (GO:0097271) 
      with IGI evidence.
    action: ACCEPT
    reason: PMID:12782684 demonstrates RAS2 recruits mitotic exit regulator Lte1
      to bud cortex.
    supported_by:
    - reference_id: PMID:12782684
      supporting_text: Jun 2. Ras recruits mitotic exit regulator Lte1 to the 
        bud cortex in budding yeast.
- term:
    id: GO:0000411
    label: positive regulation of transcription by galactose
  evidence_type: IMP
  original_reference_id: PMID:16292676
  review:
    summary: Curation review of positive regulation of transcription by 
      galactose (GO:0000411) with IMP evidence.
    action: UNDECIDED
    reason: Insufficient information on mechanism. Paper addresses 
      phosphoglucomutase activity and metabolic effects rather than direct 
      transcriptional regulation.
    supported_by:
    - reference_id: PMID:16292676
      supporting_text: Increased phosphoglucomutase activity suppresses the 
        galactose growth defect associated with elevated levels of Ras signaling
        in S.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:8106517
  review:
    summary: Curation review of GTPase activity (GO:0003924) with IDA evidence 
      from biochemical characterization study.
    action: ACCEPT
    reason: PMID:8106517 biochemically characterizes RAS2 GTPase activity, 
      measuring intrinsic GTPase rates and GDP dissociation. Core catalytic 
      function of RAS2.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:8106517
      supporting_text: Biochemical characterization of yeast RAS2 mutants
        reveals a new region of ras protein involved in the interaction with
        GTPase-activating proteins.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        The primary Ras GEF **Cdc25** promotes GDP→GTP exchange on Ras proteins and is required for the **glucose-induced increase in Ras-GTP**
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:6438624
  review:
    summary: Curation review of GTP binding (GO:0005525) with IDA evidence from 
      foundational biochemical study.
    action: ACCEPT
    reason: PMID:6438624 demonstrates RAS2 binds guanine nucleotides (GTP/GDP) 
      with specificity characteristic of Ras proteins. Foundational evidence for
      RAS2 as GTPase.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:6438624
      supporting_text: A product of yeast RAS2 gene is a guanine nucleotide
        binding protein.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras2p cycles between an **inactive GDP-bound** state and an **active GTP-bound** state.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:22575457
  review:
    summary: Curation review of mitochondrion (GO:0005739) with IDA evidence.
    action: KEEP_AS_NON_CORE
    reason: PMID:22575457 shows minor mitochondrial localization. Not primary
      site of RAS2 signaling function. Falcon notes mitochondrial accumulation
      is enhanced under nutrient depletion.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:22575457
      supporting_text: Localization of Ras signaling complex in budding yeast.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras2p has been reported to contact the ER and accumulate at mitochondria under nutrient depletion
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:22575457
  review:
    summary: Curation review of endoplasmic reticulum membrane (GO:0005789) with
      IDA evidence.
    action: ACCEPT
    reason: PMID:22575457 demonstrates RAS2 localizes to ER membrane during
      lipid modification and trafficking to plasma membrane.
    additional_reference_ids:
    - file:yeast/RAS2/RAS2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:22575457
      supporting_text: Localization of Ras signaling complex in budding yeast.
    - reference_id: file:yeast/RAS2/RAS2-deep-research-falcon.md
      supporting_text: |-
        Ras CAAX processing includes farnesylation followed by AAX proteolysis, methylation, and palmitoylation, and farnesylation targets Ras proteins to **ER/Golgi** membranes for processing en route to the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20162532
  review:
    summary: Curation review of plasma membrane (GO:0005886) with IDA evidence.
    action: ACCEPT
    reason: Direct experimental evidence. Chemical inhibition of CaaX protease 
      disrupts RAS2 localization.
    supported_by:
    - reference_id: PMID:20162532
      supporting_text: Chemical inhibition of CaaX protease activity disrupts 
        yeast Ras localization.
- term:
    id: GO:0030437
    label: ascospore formation
  evidence_type: IMP
  original_reference_id: PMID:2558958
  review:
    summary: Curation review of ascospore formation (GO:0030437) with IMP 
      evidence.
    action: KEEP_AS_NON_CORE
    reason: RAS2 plays permissive role in sporulation response to nutrient 
      starvation. Not primary regulator of meiosis.
    supported_by:
    - reference_id: PMID:2558958
      supporting_text: Isolation and characterization of temperature-sensitive 
        mutations in the RAS2 and CYR1 genes of Saccharomyces cerevisiae.
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:15917658
  review:
    summary: Curation review of regulation of protein localization (GO:0032880) 
      with IMP evidence.
    action: ACCEPT
    reason: PMID:15917658 demonstrates RAS2 collaborates with Cdc42/Cla4 to 
      target and anchor Lte1 at bud cortex.
    supported_by:
    - reference_id: PMID:15917658
      supporting_text: Ras and the Rho effector Cla4 collaborate to target and 
        anchor Lte1 at the bud cortex.
core_functions:
- description: "RAS2 serves as the primary regulator of cAMP/PKA signaling pathway,
    acting as a molecular switch that cycles between GTP-bound active and GDP-bound
    inactive states. In the active state, RAS2-GTP binds to and activates adenylate
    cyclase (CYR1), increasing cellular cAMP levels. This triggers cAMP-dependent
    protein kinase (PKA) activation, which phosphorylates downstream targets controlling
    nutrient-dependent growth, glucose metabolism, stress resistance, and replicative
    lifespan determination."
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0007265
    label: Ras protein signal transduction
  - id: GO:0042149
    label: cellular response to glucose starvation
  supported_by:
  - reference_id: PMID:6438624
    supporting_text: A product of yeast RAS2 gene is a guanine nucleotide 
      binding protein
  - reference_id: PMID:8106517
    supporting_text: Biochemical characterization of yeast RAS2 reveals GTPase 
      activity and interactions with GTPase-activating proteins
    full_text_unavailable: true
  - reference_id: PMID:15016820
    supporting_text: The Ras/cAMP-dependent protein kinase signaling pathway 
      regulates nutrient starvation response
    full_text_unavailable: true
- description: "RAS2 functions in morphogenetic signaling through the Cdc42/MAPK pathway
    to regulate cell division polarity and pseudohyphal growth. Upon nutrient starvation,
    activated RAS2 signals through Cdc42 and the MAPK cascade (Ste20/Ste11/Ste7) to
    induce filamentous growth and coordinate unipolar budding pattern characteristic
    of pseudohyphae. This allows nutrient foraging in diploid cells."
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  directly_involved_in:
  - id: GO:2000222
    label: positive regulation of pseudohyphal growth
  - id: GO:0007163
    label: establishment or maintenance of cell polarity
  supported_by:
  - reference_id: PMID:1547504
    supporting_text: Unipolar cell divisions in yeast S. cerevisiae lead to 
      filamentous growth regulated by starvation and RAS
    full_text_unavailable: true
  - reference_id: PMID:8643578
    supporting_text: Ras2 signals via the Cdc42/Ste20/mitogen-activated protein 
      kinase module to induce filamentous growth
- description: "RAS2 regulates protein localization to the bud neck and cell division
    machinery. RAS2-GTP recruits and anchors mitotic exit regulators (including Lte1)
    to the bud cortex in a Cdc42-dependent manner, controlling cell polarity and ensuring
    proper cytokinesis."
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0097271
    label: protein localization to bud neck
  - id: GO:0032880
    label: regulation of protein localization
  supported_by:
  - reference_id: PMID:12782684
    supporting_text: Ras recruits mitotic exit regulator Lte1 to the bud cortex 
      in budding yeast
  - reference_id: PMID:15917658
    supporting_text: Ras and the Rho effector Cla4 collaborate to target and 
      anchor Lte1 at the bud cortex
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11805837
  title: Systematic identification of protein complexes in Saccharomyces 
    cerevisiae by mass spectrometry.
  findings: []
- id: PMID:11914276
  title: Subcellular localization of the yeast proteome.
  findings: []
- id: PMID:12782684
  title: Ras recruits mitotic exit regulator Lte1 to the bud cortex in budding 
    yeast.
  findings: []
- id: PMID:15016820
  title: The Ras/cAMP-dependent protein kinase signaling pathway regulates an 
    early step of the autophagy process in Saccharomyces cerevisiae.
  findings: []
- id: PMID:1547504
  title: 'Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth:
    regulation by starvation and RAS.'
  findings: []
- id: PMID:15917658
  title: Ras and the Rho effector Cla4 collaborate to target and anchor Lte1 at 
    the bud cortex.
  findings: []
- id: PMID:16292676
  title: Increased phosphoglucomutase activity suppresses the galactose growth 
    defect associated with elevated levels of Ras signaling in S. cerevisiae.
  findings: []
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces 
    cerevisiae.
  findings: []
- id: PMID:16622836
  title: The plasma membrane proteome of Saccharomyces cerevisiae and its 
    response to the antifungal calcofluor.
  findings: []
- id: PMID:20162532
  title: Chemical inhibition of CaaX protease activity disrupts yeast Ras 
    localization.
  findings: []
- id: PMID:21073870
  title: Feedback regulation of Ras2 guanine nucleotide exchange factor 
    (Ras2-GEF) activity of Cdc25p by Cdc25p phosphorylation in the yeast 
    Saccharomyces cerevisiae.
  findings: []
- id: PMID:21457714
  title: The membrane localization of Ras2p and the association between Cdc25p 
    and Ras2-GTP are regulated by protein kinase A (PKA) in the yeast 
    Saccharomyces cerevisiae.
  findings: []
- id: PMID:21925385
  title: The cAMP-dependent protein kinase signaling pathway is a key regulator 
    of P body foci formation.
  findings: []
- id: PMID:22575457
  title: Localization of Ras signaling complex in budding yeast.
  findings: []
- id: PMID:23127800
  title: Live-cell imaging of endogenous Ras-GTP shows predominant Ras 
    activation at the plasma membrane and in the nucleus in Saccharomyces 
    cerevisiae.
  findings: []
- id: PMID:23831759
  title: Mapping the functional yeast ABC transporter interactome.
  findings: []
- id: PMID:24769239
  title: Quantitative variations of the mitochondrial proteome and 
    phosphoproteome during fermentative and respiratory growth in Saccharomyces 
    cerevisiae.
  findings: []
- id: PMID:2558958
  title: Isolation and characterization of temperature-sensitive mutations in 
    the RAS2 and CYR1 genes of Saccharomyces cerevisiae.
  findings: []
- id: PMID:26928762
  title: 'One library to make them all: streamlining the creation of yeast libraries
    via a SWAp-Tag strategy.'
  findings: []
- id: PMID:6438624
  title: A product of yeast RAS2 gene is a guanine nucleotide binding protein.
  findings: []
- id: PMID:8106517
  title: Biochemical characterization of yeast RAS2 mutants reveals a new region
    of ras protein involved in the interaction with GTPase-activating proteins.
  findings: []
- id: PMID:8643578
  title: Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase
    module to induce filamentous growth in Saccharomyces cerevisiae.
  findings: []
- id: file:yeast/RAS2/RAS2-deep-research-falcon.md
  title: Falcon deep research report on RAS2 (Saccharomyces cerevisiae)
  findings:
  - statement: |
      RAS2 (Ras2p) is a 322-residue Ras-family small GTPase that acts as a
      molecular switch, cycling between an inactive GDP-bound state and an
      active GTP-bound state under control of upstream GEFs and GAPs.
    supporting_text: |-
      Ras2p cycles between an **inactive GDP-bound** state and an **active GTP-bound** state. This GTPase cycle is central to Ras2p’s signaling role and is controlled by upstream regulators (GEFs and GAPs).
    reference_section_type: OTHER
  - statement: |
      The primary biochemical function of RAS2 is activation of adenylate
      cyclase (Cyr1/CDC35) to produce cAMP, which binds Bcy1 to activate the
      PKA catalytic subunits Tpk1/2/3, defining the core Ras-cAMP-PKA pathway
      that controls growth and metabolism.
    supporting_text: |-
      In budding yeast, both Ras1p and Ras2p act upstream of **adenylate cyclase (Cyr1/CDC35)** to stimulate **cAMP** production; cAMP then binds the regulatory subunit **Bcy1** to activate **PKA catalytic subunits Tpk1/2/3**, establishing the core **Ras–cAMP–PKA** pathway that controls growth and metabolism.
    reference_section_type: OTHER
  - statement: |
      RAS2-GTP levels are set by the GEF Cdc25 (required for glucose-induced
      Ras-GTP increase) and the GAPs Ira1 and Ira2, which stimulate intrinsic
      GTP hydrolysis and negatively regulate cAMP output.
    supporting_text: |-
      The primary Ras GEF **Cdc25** promotes GDP→GTP exchange on Ras proteins and is required for the **glucose-induced increase in Ras-GTP**; temperature-sensitive cdc25 mutants show reduced intracellular cAMP and reduced adenylate cyclase activity
    reference_section_type: OTHER
  - statement: |
      RAS2 membrane targeting depends on CAAX processing: it is farnesylated
      at Cys319 and palmitoylated at Cys318; farnesylation is required for
      plasma membrane localization and effector recruitment, and loss of
      palmitoylation (C318S) mislocalizes Ras2p to the cytoplasm.
    supporting_text: |-
      Ras2p is reported to be **farnesylated at Cys319** and **palmitoylated at Cys318**; **farnesylation** is required for efficient **plasma membrane localization** and effector recruitment, whereas loss of palmitoylation (C318S) mislocalizes Ras2p to the cytoplasm in the cited work.
    reference_section_type: OTHER
  - statement: |
      Activation of Cyr1 by RAS2 occurs at the plasma membrane, although RAS2
      and its partners are also observed on endomembranes, contacting the ER
      and accumulating at mitochondria under nutrient depletion, with nuclear
      active Ras2 reported in invasive growth contexts.
    supporting_text: |-
      While Ras2p and its regulators/partners have been observed on **endomembranes**, the activation of Cyr1 by Ras2 that drives cAMP production is described as occurring at the **plasma membrane**.
    reference_section_type: OTHER
  - statement: |
      RAS2 is a dominant controller of glucose-responsive transcription,
      accounting for nearly ~90% of the transcriptional changes observed upon
      glucose addition.
    supporting_text: |-
      Ras2-driven Ras/cAMP/PKA signaling is described as accounting for **nearly ~90%** of the transcriptional changes observed upon glucose addition, placing Ras2 as a dominant controller of glucose-responsive transcriptional reprogramming.
    reference_section_type: OTHER
  - statement: |
      RAS1 and RAS2 double loss is lethal while single deletions are viable on
      glucose; ras2Delta strains show defects in growth on nonfermentable
      carbon sources.
    supporting_text: |-
      Yeast has two Ras genes (**RAS1** and **RAS2**). Loss of both is **lethal**, consistent with an essential requirement for Ras-dependent activation of the cAMP/PKA pathway, while single deletions are viable under standard glucose conditions.
    reference_section_type: OTHER
  - statement: |
      RAS2 influences filamentous/invasive growth and cell-fate decisions,
      linking Ras2/cAMP/PKA signaling to differentiation outputs including
      Flo8-linked programs.
    supporting_text: |-
      Ras2 influences filamentous/invasive growth and broader “cell fate” decisions; the corpus links Ras2/cAMP/PKA signaling to differentiation outputs (including Flo8-linked programs) and provides a localization-focused treatment of nuclear active Ras2 in invasive growth.
    reference_section_type: OTHER
  - statement: |
      RAS2 is best interpreted as a central nutrient-state integrator,
      positioned at the interface between extracellular nutrient cues
      (especially glucose) and broad intracellular programs for growth, stress
      protection, and differentiation.
    supporting_text: |-
      Ras2p is best interpreted as a **central nutrient-state integrator**: upstream regulators (Cdc25; Ira1/2; additional modulators such as Gpb1/2) determine the fraction of Ras2p in the GTP-bound state, which is then transduced primarily by Cyr1 into cAMP dynamics and PKA activation.
    reference_section_type: OTHER

GO Term	Evidence	Action	Reason
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Curation review of plasma membrane (GO:0005886) with IBA evidence. RAS2 is farnesylated at Cys319 and palmitoylated at Cys318; farnesylation is required for efficient plasma membrane localization, the site at which RAS2 activates Cyr1 to drive cAMP production. Reason: IBA annotation confirmed by multiple IDA annotations. RAS2 is farnesylated and palmitoylated, essential for plasma membrane anchoring. Supporting Evidence: file:yeast/RAS2/RAS2-deep-research-falcon.md Ras2p is reported to be farnesylated at Cys319 and palmitoylated at Cys318; farnesylation is required for efficient plasma membrane localization and effector recruitment file:yeast/RAS2/RAS2-deep-research-falcon.md the activation of Cyr1 by Ras2 that drives cAMP production is described as occurring at the plasma membrane.
GO:0007163 establishment or maintenance of cell polarity	IBA GO_REF:0000033	ACCEPT	Summary: Curation review of establishment or maintenance of cell polarity (GO:0007163) with IBA evidence. Reason: RAS2 regulates cell polarity through protein localization to bud neck and Cdc42/MAPK signaling pathway controlling cell division morphogenesis.
GO:0007265 Ras protein signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: Curation review of Ras protein signal transduction (GO:0007265) with IBA evidence. RAS2-GTP activates adenylate cyclase (Cyr1/CDC35) to raise cAMP, which binds Bcy1 to activate PKA catalytic subunits Tpk1/2/3, establishing the core Ras-cAMP-PKA pathway. Reason: Core function of RAS2. Acts as primary regulator of adenylate cyclase and PKA signaling pathway. Supporting Evidence: file:yeast/RAS2/RAS2-deep-research-falcon.md both Ras1p and Ras2p act upstream of adenylate cyclase (Cyr1/CDC35) to stimulate cAMP production; cAMP then binds the regulatory subunit Bcy1 to activate PKA catalytic subunits Tpk1/2/3, establishing the core Ras–cAMP–PKA pathway that controls growth and metabolism.
GO:0003924 GTPase activity	IBA GO_REF:0000033	ACCEPT	Summary: Curation review of GTPase activity (GO:0003924) with IBA evidence. RAS2 acts as a molecular switch cycling between an inactive GDP-bound state and an active GTP-bound state; this GTPase cycle is controlled by the GEF Cdc25 and the GAPs Ira1/Ira2. Reason: Core catalytic function. RAS2 hydrolyzes GTP to GDP, enabling regulation of downstream signaling. Supporting Evidence: file:yeast/RAS2/RAS2-deep-research-falcon.md Ras2p cycles between an inactive GDP-bound state and an active GTP-bound state. file:yeast/RAS2/RAS2-deep-research-falcon.md Ira1 and Ira2 stimulate Ras intrinsic GTP hydrolysis (GAP activity) and thus negatively regulate Ras2-driven cAMP output
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: Curation review of nucleotide binding (GO:0000166) with IEA evidence. Reason: Appropriate computational annotation. RAS2 binds guanine nucleotides (GTP/GDP) as substrate for catalytic cycle.
GO:0003924 GTPase activity	IEA GO_REF:0000120	ACCEPT	Summary: Curation review of GTPase activity (GO:0003924) with IEA evidence. Reason: Valid InterPro-based inference. Multiple evidence types acceptable for same term.
GO:0003925 G protein activity	IEA GO_REF:0000003	ACCEPT	Summary: Curation review of G protein activity (GO:0003925) with IEA evidence. Reason: Appropriate parent term. RAS2 is a GTP-binding protein with GTPase activity (G protein).
GO:0005525 GTP binding	IEA GO_REF:0000120	ACCEPT	Summary: Curation review of GTP binding (GO:0005525) with IEA evidence. Reason: Appropriate computational annotation. RAS2 canonical substrate is GTP.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Curation review of plasma membrane (GO:0005886) with IEA evidence. Reason: Consistent with IBA and IDA evidence from subcellular localization mapping.
GO:0007165 signal transduction	IEA GO_REF:0000002	ACCEPT	Summary: Curation review of signal transduction (GO:0007165) with IEA evidence. Reason: Appropriate parent term for RAS2 signaling function.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: Curation review of membrane (GO:0016020) with IEA evidence. Reason: Appropriate parent term. RAS2 is a membrane-anchored protein.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: Curation review of hydrolase activity (GO:0016787) with IEA evidence. Reason: Appropriate parent term for GTPase activity (hydrolysis of phosphodiester bonds).
GO:0097271 protein localization to bud neck	IEA GO_REF:0000117	REMOVE	Summary: Curation review of protein localization to bud neck (GO:0097271) with IEA evidence. Reason: IEA annotation for specific subcellular localization is overly detailed for computational inference. Specific experimental evidence (IGI) already provided.
GO:0005515 protein binding	IPI PMID:11805837 Systematic identification of protein complexes in Saccharomy...	REMOVE	Summary: Curation review of protein binding (GO:0005515) with IPI evidence. Reason: Generic protein binding term is non-informative. RAS1 interaction is properly described by signal transduction and protein localization terms. Remove per GO guidelines. Supporting Evidence: PMID:11805837 Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry.
GO:0005515 protein binding	IPI PMID:12782684 Ras recruits mitotic exit regulator Lte1 to the bud cortex i...	REMOVE	Summary: Curation review of protein binding (GO:0005515) with IPI evidence. Reason: Generic protein binding term is non-informative. LTE1 recruitment to bud neck is captured by specific process terms (protein localization, cell division). Supporting Evidence: PMID:12782684 Jun 2. Ras recruits mitotic exit regulator Lte1 to the bud cortex in budding yeast.
GO:0005515 protein binding	IPI PMID:16554755 Global landscape of protein complexes in the yeast Saccharom...	REMOVE	Summary: Curation review of protein binding (GO:0005515) with IPI evidence. Reason: Generic protein binding term is non-informative per GO curation guidelines. Use specific process terms instead. Supporting Evidence: PMID:16554755 Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
GO:0005515 protein binding	IPI PMID:21073870 Feedback regulation of Ras2 guanine nucleotide exchange fact...	REMOVE	Summary: Curation review of protein binding (GO:0005515) with IPI evidence. Reason: Generic protein binding term is non-informative. CDC25 GEF interaction is properly described through signal transduction pathways. Supporting Evidence: PMID:21073870 Epub 2010 Nov 10. Feedback regulation of Ras2 guanine nucleotide exchange factor (Ras2-GEF) activity of Cdc25p by Cdc25p phosphorylation in the yeast Saccharomyces cerevisiae.
GO:0005515 protein binding	IPI PMID:21457714 The membrane localization of Ras2p and the association betwe...	REMOVE	Summary: Curation review of protein binding (GO:0005515) with IPI evidence. Reason: Generic protein binding term is non-informative. PKA regulation of RAS2 is captured by PKA signaling pathway terms. Supporting Evidence: PMID:21457714 Epub 2011 Mar 30. The membrane localization of Ras2p and the association between Cdc25p and Ras2-GTP are regulated by protein kinase A (PKA) in the yeast Saccharomyces cerevisiae.
GO:0005515 protein binding	IPI PMID:23831759 Mapping the functional yeast ABC transporter interactome.	REMOVE	Summary: Curation review of protein binding (GO:0005515) with IPI evidence. Reason: Generic protein binding term is non-informative. YCF1 interaction not core to RAS2 function. Supporting Evidence: PMID:23831759 Mapping the functional yeast ABC transporter interactome.
GO:0005739 mitochondrion	HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph...	KEEP AS NON CORE	Summary: Curation review of mitochondrion (GO:0005739) with HDA evidence. Reason: Minor mitochondrial localization during respiratory growth. Not primary site of RAS2 signaling. Supporting Evidence: PMID:24769239 2014 Apr 24. Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae.
GO:0071944 cell periphery	HDA PMID:26928762 One library to make them all: streamlining the creation of y...	KEEP AS NON CORE	Summary: Curation review of cell periphery (GO:0071944) with HDA evidence. Reason: General cell periphery localization. Less specific than plasma membrane. Supporting Evidence: PMID:26928762 One library to make them all: streamlining the creation of yeast libraries via a SWAp-Tag strategy.
GO:0005886 plasma membrane	HDA PMID:11914276 Subcellular localization of the yeast proteome.	ACCEPT	Summary: Curation review of plasma membrane (GO:0005886) with HDA evidence. Reason: Proteomics evidence supporting plasma membrane localization. Supporting Evidence: PMID:11914276 Subcellular localization of the yeast proteome.
GO:0005886 plasma membrane	HDA PMID:16622836 The plasma membrane proteome of Saccharomyces cerevisiae and...	ACCEPT	Summary: Curation review of plasma membrane (GO:0005886) with HDA evidence. Reason: Plasma membrane proteome study confirming RAS2 localization. Supporting Evidence: PMID:16622836 The plasma membrane proteome of Saccharomyces cerevisiae and its response to the antifungal calcofluor.
GO:0010603 regulation of cytoplasmic mRNA processing body assembly	IMP PMID:21925385 The cAMP-dependent protein kinase signaling pathway is a key...	ACCEPT	Summary: Curation review of regulation of cytoplasmic mRNA processing body assembly (GO:0010603) with IMP evidence. Reason: RAS2/PKA pathway regulates P body formation. PMID:21925385 demonstrates cAMP/PKA controls mRNA processing body assembly. Supporting Evidence: PMID:21925385 The cAMP-dependent protein kinase signaling pathway is a key regulator of P body foci formation.
GO:0042149 cellular response to glucose starvation	IMP PMID:21925385 The cAMP-dependent protein kinase signaling pathway is a key...	ACCEPT	Summary: Curation review of cellular response to glucose starvation (GO:0042149) with IMP evidence. Reason: RAS2 is critical regulator of nutrient starvation response. Loss of RAS2 leads to constitutive starvation response. RAS2-driven Ras/cAMP/PKA signaling dominates glucose-responsive transcriptional reprogramming. Supporting Evidence: PMID:21925385 The cAMP-dependent protein kinase signaling pathway is a key regulator of P body foci formation. file:yeast/RAS2/RAS2-deep-research-falcon.md Ras2-driven Ras/cAMP/PKA signaling is described as accounting for nearly ~90% of the transcriptional changes observed upon glucose addition, placing Ras2 as a dominant controller of glucose-responsive transcriptional reprogramming.
GO:0016236 macroautophagy	IGI PMID:15016820 The Ras/cAMP-dependent protein kinase signaling pathway regu...	MODIFY	Summary: Curation review of macroautophagy (GO:0016236) with IGI evidence. Reason: PMID:15016820 demonstrates RAS/PKA pathway INHIBITS autophagy during growth. Annotation reflects inhibitory relationship. Proposed replacements: negative regulation of autophagy Supporting Evidence: PMID:15016820 2004 Mar 11. The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae.
GO:0032258 cytoplasm to vacuole targeting by the Cvt pathway	IMP PMID:15016820 The Ras/cAMP-dependent protein kinase signaling pathway regu...	MODIFY	Summary: Curation review of cytoplasm to vacuole targeting by the Cvt pathway (GO:0032258) with IMP evidence. Reason: PMID:15016820 demonstrates RAS/PKA pathway INHIBITS Cvt pathway during growth. Annotation should reflect inhibitory regulation. Proposed replacements: negative regulation of cytoplasm to vacuole targeting Supporting Evidence: PMID:15016820 2004 Mar 11. The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae.
GO:2000222 positive regulation of pseudohyphal growth	IMP PMID:1547504 Unipolar cell divisions in the yeast S. cerevisiae lead to f...	ACCEPT	Summary: Curation review of positive regulation of pseudohyphal growth (GO:2000222) with IMP evidence. Reason: Well-documented. RAS2 (especially constitutively active RAS2val19) promotes pseudohyphal growth in response to nitrogen starvation. Supporting Evidence: PMID:1547504 Unipolar cell divisions in the yeast S.
GO:2000222 positive regulation of pseudohyphal growth	IMP PMID:8643578 Ras2 signals via the Cdc42/Ste20/mitogen-activated protein k...	ACCEPT	Summary: Curation review of positive regulation of pseudohyphal growth (GO:2000222) with IMP evidence. Reason: PMID:8643578 demonstrates RAS2 signals via Cdc42/MAPK pathway to induce filamentous growth. Supporting Evidence: PMID:8643578 Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae. file:yeast/RAS2/RAS2-deep-research-falcon.md Ras2 influences filamentous/invasive growth and broader “cell fate” decisions; the corpus links Ras2/cAMP/PKA signaling to differentiation outputs (including Flo8-linked programs)
GO:0005634 nucleus	IDA PMID:23127800 Live-cell imaging of endogenous Ras-GTP shows predominant Ra...	ACCEPT	Summary: Curation review of nucleus (GO:0005634) with IDA evidence. Reason: PMID:23127800 demonstrates RAS2-GTP localizes to nucleus, supporting transcriptional regulation functions. Supporting Evidence: PMID:23127800 Live-cell imaging of endogenous Ras-GTP shows predominant Ras activation at the plasma membrane and in the nucleus in Saccharomyces cerevisiae. file:yeast/RAS2/RAS2-deep-research-falcon.md a dissertation-level source in the corpus further focuses on evidence for nuclear active Ras2 in invasive growth contexts.
GO:0005886 plasma membrane	IDA PMID:23127800 Live-cell imaging of endogenous Ras-GTP shows predominant Ra...	ACCEPT	Summary: Curation review of plasma membrane (GO:0005886) with IDA evidence. Reason: Direct experimental evidence for plasma membrane localization confirmed by fluorescence imaging. Supporting Evidence: PMID:23127800 Live-cell imaging of endogenous Ras-GTP shows predominant Ras activation at the plasma membrane and in the nucleus in Saccharomyces cerevisiae.
GO:0097271 protein localization to bud neck	IGI PMID:12782684 Ras recruits mitotic exit regulator Lte1 to the bud cortex i...	ACCEPT	Summary: Curation review of protein localization to bud neck (GO:0097271) with IGI evidence. Reason: PMID:12782684 demonstrates RAS2 recruits mitotic exit regulator Lte1 to bud cortex. Supporting Evidence: PMID:12782684 Jun 2. Ras recruits mitotic exit regulator Lte1 to the bud cortex in budding yeast.
GO:0000411 positive regulation of transcription by galactose	IMP PMID:16292676 Increased phosphoglucomutase activity suppresses the galacto...	UNDECIDED	Summary: Curation review of positive regulation of transcription by galactose (GO:0000411) with IMP evidence. Reason: Insufficient information on mechanism. Paper addresses phosphoglucomutase activity and metabolic effects rather than direct transcriptional regulation. Supporting Evidence: PMID:16292676 Increased phosphoglucomutase activity suppresses the galactose growth defect associated with elevated levels of Ras signaling in S.
GO:0003924 GTPase activity	IDA PMID:8106517 Biochemical characterization of yeast RAS2 mutants reveals a...	ACCEPT	Summary: Curation review of GTPase activity (GO:0003924) with IDA evidence from biochemical characterization study. Reason: PMID:8106517 biochemically characterizes RAS2 GTPase activity, measuring intrinsic GTPase rates and GDP dissociation. Core catalytic function of RAS2. Supporting Evidence: PMID:8106517 Biochemical characterization of yeast RAS2 mutants reveals a new region of ras protein involved in the interaction with GTPase-activating proteins. file:yeast/RAS2/RAS2-deep-research-falcon.md The primary Ras GEF Cdc25 promotes GDP→GTP exchange on Ras proteins and is required for the glucose-induced increase in Ras-GTP
GO:0005525 GTP binding	IDA PMID:6438624 A product of yeast RAS2 gene is a guanine nucleotide binding...	ACCEPT	Summary: Curation review of GTP binding (GO:0005525) with IDA evidence from foundational biochemical study. Reason: PMID:6438624 demonstrates RAS2 binds guanine nucleotides (GTP/GDP) with specificity characteristic of Ras proteins. Foundational evidence for RAS2 as GTPase. Supporting Evidence: PMID:6438624 A product of yeast RAS2 gene is a guanine nucleotide binding protein. file:yeast/RAS2/RAS2-deep-research-falcon.md Ras2p cycles between an inactive GDP-bound state and an active GTP-bound state.
GO:0005739 mitochondrion	IDA PMID:22575457 Localization of Ras signaling complex in budding yeast.	KEEP AS NON CORE	Summary: Curation review of mitochondrion (GO:0005739) with IDA evidence. Reason: PMID:22575457 shows minor mitochondrial localization. Not primary site of RAS2 signaling function. Falcon notes mitochondrial accumulation is enhanced under nutrient depletion. Supporting Evidence: PMID:22575457 Localization of Ras signaling complex in budding yeast. file:yeast/RAS2/RAS2-deep-research-falcon.md Ras2p has been reported to contact the ER and accumulate at mitochondria under nutrient depletion
GO:0005789 endoplasmic reticulum membrane	IDA PMID:22575457 Localization of Ras signaling complex in budding yeast.	ACCEPT	Summary: Curation review of endoplasmic reticulum membrane (GO:0005789) with IDA evidence. Reason: PMID:22575457 demonstrates RAS2 localizes to ER membrane during lipid modification and trafficking to plasma membrane. Supporting Evidence: PMID:22575457 Localization of Ras signaling complex in budding yeast. file:yeast/RAS2/RAS2-deep-research-falcon.md Ras CAAX processing includes farnesylation followed by AAX proteolysis, methylation, and palmitoylation, and farnesylation targets Ras proteins to ER/Golgi membranes for processing en route to the plasma membrane.
GO:0005886 plasma membrane	IDA PMID:20162532 Chemical inhibition of CaaX protease activity disrupts yeast...	ACCEPT	Summary: Curation review of plasma membrane (GO:0005886) with IDA evidence. Reason: Direct experimental evidence. Chemical inhibition of CaaX protease disrupts RAS2 localization. Supporting Evidence: PMID:20162532 Chemical inhibition of CaaX protease activity disrupts yeast Ras localization.
GO:0030437 ascospore formation	IMP PMID:2558958 Isolation and characterization of temperature-sensitive muta...	KEEP AS NON CORE	Summary: Curation review of ascospore formation (GO:0030437) with IMP evidence. Reason: RAS2 plays permissive role in sporulation response to nutrient starvation. Not primary regulator of meiosis. Supporting Evidence: PMID:2558958 Isolation and characterization of temperature-sensitive mutations in the RAS2 and CYR1 genes of Saccharomyces cerevisiae.
GO:0032880 regulation of protein localization	IMP PMID:15917658 Ras and the Rho effector Cla4 collaborate to target and anch...	ACCEPT	Summary: Curation review of regulation of protein localization (GO:0032880) with IMP evidence. Reason: PMID:15917658 demonstrates RAS2 collaborates with Cdc42/Cla4 to target and anchor Lte1 at bud cortex. Supporting Evidence: PMID:15917658 Ras and the Rho effector Cla4 collaborate to target and anchor Lte1 at the bud cortex.