GO_REF:0000033

Annotation inferences using phylogenetic trees

IBA annotations are based on phylogenetic analysis showing CG6051 is orthologous to human ZFYVE28/LST2

"Phylogenetic analysis supports functional conservation between fly CG6051 and human ZFYVE28"

GO_REF:0000043

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

Zinc-finger keyword supports zinc ion binding annotation

"UniProt keywords include zinc-finger based on FYVE domain"

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

Multiple incorrect phosphatase annotations that should be removed

"ARBA incorrectly predicted phosphatase activities based on domain misinterpretation"
Correct molecular adaptor activity annotation

"ARBA correctly identified molecular adaptor function"

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Generic metal ion binding annotation that should be more specific

"Combined methods identified metal binding but not the specific zinc requirement"

PMID:39141345

mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR

Q9VB70

UniProt entry for CG6051

FYVE zinc finger domain at positions 909-969

"ZN_FING 909..969 /note="FYVE-type""
Eight zinc-coordinating residues identified

"BINDING sites for Zn(2+) at positions 915, 918, 931, 934, 939, 942, 961, 964"
Phosphorylation sites at S549, S550, S810

"MOD_RES 549, 550, 810 /note="Phosphoserine""
No phosphatase domains annotated

"UniProt functional annotation identifies it as Lateral signaling target protein 2 homolog, not a phosphatase"

file:DROME/CG6051/CG6051-deep-research.md

Deep research on CG6051 gene function

CG6051 is orthologous to human ZFYVE28/LST2

"CG6051 is orthologous to human ZFYVE28 (also called LST2)"
Functions in negative regulation of EGFR signaling

"LST2 helps inhibit the upstream EGF receptor (EGFR) signaling pathway"
FYVE domain binds PI3P on early endosomes

"FYVE domain typically binds phosphatidylinositol 3-phosphate (PI3P) on endosomal membranes"
Not a phosphatase but an adaptor protein

"LST2 is NOT a phosphatase itself but rather acts as an adaptor/scaffold protein"

file:DROME/CG6051/CG6051-bioinformatics/RESULTS.md

Bioinformatics analysis of CG6051

Confirmed FYVE zinc finger domain at positions 909-969

"FYVE domain found at positions 909-969 with all expected cysteines"
No phosphatase domains detected

"No canonical phosphatase active sites or domains found"
No TOS motif found unlike human ortholog

"CG6051 lacks the TOS motif present in human LST2 at positions 401-405"
Low sequence identity with human LST2 but conserved domain architecture

"Only 5-6% sequence identity but both have C-terminal FYVE domains"

file:DROME/CG6051/CG6051-hypotheses/function-hypothesis-go-0004438/openscientist.md

OpenScientist focused review of CG6051 PI3P phosphatase activity hypothesis

OpenScientist judged the CG6051 PI3P phosphatase activity hypothesis over-annotated/refuted.
The report found FYVE-domain PI3P binding but no phosphatase catalytic domain, CX5R-like active site, or non-IEA evidence for phosphatase activity.
The report recommended removing phosphatase and phosphatidylinositol dephosphorylation annotations while retaining early-endosome/adaptor biology and considering PI3P binding.

file:DROME/CG6051/CG6051-deep-research-falcon.md

Falcon (Edison) deep research report on CG6051/Q9VB70 function

CG6051/Q9VB70 belongs to the lst-2/LST2 family with FYVE-type zinc finger domain architecture, implicating PI3P-linked endosomal membrane association and RTK signaling/trafficking control, based on family-level inference from mammalian LST2 and nematode lst-2 rather than direct fly experiments.

"CG6051 (UniProt Q9VB70) is annotated as a **lateral signaling target protein 2 (LST2) homolog** in *Drosophila melanogaster* and belongs to the **lst-2/LST2 family** with an **FYVE-type zinc finger (FYVE_LST2-related) domain architecture**, implicating it in **phosphatidylinositol-3-phosphate (PI3P)–linked endosomal membrane association** and **receptor tyrosine kinase (RTK) signaling/trafficking control**"
A 2024 PNAS study explicitly lists Drosophila Q9VB70 as an LST2 homolog, supporting family-level transfer of function, but fly-specific mechanistic literature directly testing CG6051/Q9VB70 is sparse.

"a PNAS study that provides detailed biochemical/structural/cell-biological evidence for **mammalian LST2 (ZFYVE28) as an mTORC1 substrate and a negative regulator of EGFR**, and importantly **explicitly includes the *Drosophila* homolog as UniProt Q9VB70** in cross-species analysis"
The isolated human LST2 FYVE domain colocalizes with early endosomes, consistent with PI3P-driven endosomal recruitment; fly localization is inferred from domain architecture, not directly demonstrated.

"the **isolated FYVE domain colocalizes with early endosomes** (cell biological evidence), consistent with PI3P-driven endosomal recruitment."
No catalytic activity is evidenced; the strongest family data support a non-enzymatic adapter/regulator role influencing RTK abundance/signaling.

"No catalytic activity is evidenced in retrieved texts. The strongest mechanistic data for the family (human LST2) support a role as a **regulatory protein** influencing RTK abundance/signaling"
WormBook genetics place C. elegans lst-2 among lateral signaling targets acting as a modulator rather than a core RTK pathway component (Muv only in combination with gap-1), supporting a modulatory EGFR/Ras role.

"This supports an expert view that lst-2 family proteins function as **modulators** rather than core RTK pathway components, likely influencing signaling output via membrane/trafficking context."
The mTORC1 TOS-motif/RAPTOR-binding mechanism may not be conserved in Drosophila, since the TOS motif is reported conserved only in vertebrates; fly mTORC1-feedback involvement is untested in retrieved literature.

"the study notes that the **TOS motif is conserved in vertebrates**, raising the possibility that RAPTOR–TOS binding and the exact phosphorylation logic may not be conserved in *Drosophila*."
A 2016 fly RNAi screen lists CG6051 among spliceosome-complex genes required for germline stem cell homeostasis, but a figure label discrepancy (CG6051 vs CG6015) leaves the gene-identity assignment to Q9VB70 uncertain.

"a 2016 fly RNAi screen lists CG6051 among spliceosome-complex genes required for germline stem cell self-renewal/early differentiation, but the figure appears to label CG6015, so assignment to Q9VB70 is uncertain"