ProtNLM2 External predictions
View prediction review YAML · AFAP1L2-protnlm-predictions-review.yaml · Review status: COMPLETE
ProtNLM2 emitted nine GO terms for the horse AFAP1L2 transcript model A0A9L0RQI4, a PANTHER PTHR14338:SF4 member that retains every characterized human XB130 region. All nine terms are already carried in GOA by another product of the horse AFAP1L2 gene (A0A3Q2HBW2), by PAINT IBA from node PTN002682769 and/or Ensembl Compara ortholog transfer from human Q8N4X5, so none is novel. Seven are supported by human and rodent XB130 experiments within the same 1:1 ortholog subfamily (CNN): protein tyrosine kinase activator activity, SH2 and SH3 domain binding, regulation of the mitotic cell cycle, regulation of IL-6 production, positive regulation of IL-8 production and positive regulation of EGFR signaling. Two are over-broad readings of downstream signaling outputs of a cytoplasmic adaptor (NPI): positive regulation of DNA-templated transcription and inflammatory response; mouse knockout studies further show that XB130 loss enhances, rather than reduces, in vivo inflammatory injury.
Source documents: projects/PROTNLM_EVALUATION/mammal-benchmark/horse40-predictions.csv · projects/PROTNLM_EVALUATION/mammal-benchmark/predictions.jsonl.gz · projects/PROTNLM_EVALUATION/mammal-benchmark/paired-sequences/AFAP1L2.json · genes/HORSE/AFAP1L2/AFAP1L2-ai-review.yaml · genes/human/AFAP1L2/AFAP1L2-ai-review.yaml · interpro/panther/PTHR14338/PTHR14338-paint.tsv
Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by Ensembl Compara transfer from human Q8N4X5, whose IDA rests on Xu et al. 2007. In human BEAS-2B airway cells XB130 siRNA reduced IL-6 protein, and in Xb130 knockout mice serum IL-6 stayed elevated after LPS, so XB130 signaling does modulate IL-6 output, in a context-dependent direction. The unsigned regulation term fits both observations. The horse model is in the same 1:1 ortholog subfamily (PTHR14338:SF4) and retains the N-terminal SH2/SH3-binding region through which XB130 signals. The human gene review keeps this as a supported, non-core downstream output.
Supporting Evidence:
- file:human/AFAP1L2/AFAP1L2-Xu2007-excerpt.md: "In addition to IL-8, the protein level of IL-6 was also reduced by siRNA treatment."
- PMID:27029000: "The levels of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6 and interleukin-10 in the serum were significantly higher in KO mice at Day 2."
- file:HORSE/AFAP1L2/AFAP1L2-uniprot.txt: "DR PANTHER; PTHR14338:SF4; ACTIN FILAMENT-ASSOCIATED PROTEIN 1-LIKE 2; 1."
- file:HORSE/AFAP1L2/AFAP1L2-bioinformatics/RESULTS-rereview.md: "| N-terminal SH2/SH3-binding region (1-167) | 12-178 | 167/167 | 145/167 |"
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
CURATION MISTAKE
Review rationale: The term is carried in GOA on the horse AFAP1L2 product A0A3Q2HBW2 (IBA from PTN002682769 and Compara IEA), both seeded by the human IDA from Xu et al. 2007, so it is not novel; the issue is correctness. The underlying experiment shows only that XB130 enhances Src-dependent SRE/AP-1 reporter activity. AFAP1L2 is a cytoplasmic adaptor with no DNA-binding domain or nuclear role, and the reporter gain is a distal readout of its Src-activating activity. The human gene review marks both the IDA and IBA rows over-annotated on these grounds, which equally refute the prediction for the horse ortholog. The adaptor's real contribution is captured by protein tyrosine kinase activator activity.
Supporting Evidence:
- PMID:17412687: "XB130 expression in HEK293 cells enhanced serum response element- and AP-1-dependent transcriptional activation mediated by c-Src."
- file:HORSE/AFAP1L2/AFAP1L2-uniprot.txt: "DR PANTHER; PTHR14338:SF4; ACTIN FILAMENT-ASSOCIATED PROTEIN 1-LIKE 2; 1."
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by IBA from PAINT node PTN002682769 and by Compara transfer from human Q8N4X5. Independent human studies show altered cell cycles after XB130 knockdown (Xu 2007) and G1 arrest when XB130 or its Tks5 interaction is lost (Moodley 2015), downstream of Src-PI3K-Akt signaling. The horse model sits inside the PAINT clade and the same 1:1 ortholog subfamily, so the inherited regulatory role is a justified transfer. The human review keeps the term as a supported but non-core upstream signaling role.
Supporting Evidence:
- PMID:17412687: "Down-regulation of endogenous XB130 with siRNA reduced c-Src activity, IL-8 production, EGF-induced phosphorylation of Akt and GSK3beta, and altered cell cycles in human lung epithelial cells."
- PMID:26446840: "down-regulation of XB130 and/or Tks5 reduced cell proliferation, resulting in cell cycle inhibition at the G1 phase"
- file:interpro/panther/PTHR14338/PTHR14338-paint.tsv: "PTHR14338 PTN002682769 GO:0007346 P IBD"
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by IBA from PAINT node PTN002682769 and by Compara transfer, and the horse gene review records it as the first core function. Human XB130 co-expression activates c-Src, and endogenous depletion lowers c-Src activity and blocks serum/EGF-induced Src activation. The node is confined to the AFAP1L2 subfamily (PTHR14338:SF4), which contains the horse model, so the transfer is phylogenetically justified. The term correctly describes a kinase activator, not a kinase.
Supporting Evidence:
- PMID:17412687: "Their co-expression in COS-7 cells resulted in activation of c-Src and elevated tyrosine phosphorylation of multiple proteins, including XB130 itself."
- PMID:26446840: "down-regulation of XB130 and/or Tks5 inhibited serum- and growth factor-induced Src activation"
- file:interpro/panther/PTHR14338/PTHR14338-paint.tsv: "PTHR14338 PTN002682769 GO:0030296 F IBD"
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by Ensembl Compara transfer from human Q8N4X5. In human airway epithelial cells XB130 knockdown reduced IL-8 production, which supports the positive sign. The horse model is in the same 1:1 ortholog subfamily and retains the N-terminal signaling region. The human review keeps this as a supported, context-specific and non-core downstream output of Src signaling.
Supporting Evidence:
- PMID:17412687: "Down-regulation of endogenous XB130 with siRNA reduced c-Src activity, IL-8 production"
- file:HORSE/AFAP1L2/AFAP1L2-uniprot.txt: "DR PANTHER; PTHR14338:SF4; ACTIN FILAMENT-ASSOCIATED PROTEIN 1-LIKE 2; 1."
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by Compara transfer from the human IPI. Human XB130 carries N-terminal SH2-binding phosphotyrosine motifs needed for Src signaling, and Tyr54 docks the p85alpha SH2 domains; the horse model retains the whole N-terminal region and the equivalent tyrosine (Tyr65). AFAP1L2 binds SH2 domains rather than containing one. The more specific PI3K regulatory subunit binding activity is proposed in the horse review but not yet in GOA, so the prediction is not scored as less precise.
Supporting Evidence:
- PMID:17412687: "XB130DeltaN, an N-terminal deletion mutant lacking a putative SH3-binding motif and several putative SH2-binding sites, reduced its ability to mediate Src signal transduction."
- file:HORSE/AFAP1L2/AFAP1L2-bioinformatics/RESULTS-rereview.md: "| Tyr54 (p85 SH2-binding phosphosite) | 65-65 | 1/1 | 1/1 |"
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by Compara transfer from the human IPI. The polyproline-rich N-terminus of human XB130 is bound by the fifth SH3 domain of Tks5, and deleting the region carrying the SH3-binding motif impairs Src signaling. The horse model retains the full N-terminal region (167/167 paired residues) within the same ortholog subfamily, supporting transfer of this binding activity.
Supporting Evidence:
- PMID:26446840: "Structure-function studies showed that the fifth SH3 domain of Tks5 binds to the N-terminus of XB130, which contains polyproline-rich motifs."
- file:HORSE/AFAP1L2/AFAP1L2-bioinformatics/RESULTS-rereview.md: "| N-terminal SH2/SH3-binding region (1-167) | 12-178 | 167/167 | 145/167 |"
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
CURATION MISTAKE
Review rationale: The term is carried in GOA on the horse AFAP1L2 product A0A3Q2HBW2 (IBA from PTN002682769 and Compara IEA), seeded by a human IDA from Xu et al. 2007, so it is not novel; the issue is correctness. That experiment measures reduced IL-8 and IL-6 release from cultured airway epithelial cells, which is captured at the right specificity by the cytokine-production terms and does not show that XB130 does any of the work of an inflammatory response. The human gene review marks both rows over-annotated on these grounds. In vivo, Xb130 knockout mice show enhanced, not reduced, LPS-induced cytokine production and lung injury, and more inflammatory skin injury after TPA, so the cell-line result does not generalize to a pro-inflammatory role. The prediction propagates an over-broad annotation.
Supporting Evidence:
- PMID:17412687: "Down-regulation of endogenous XB130 with siRNA reduced c-Src activity, IL-8 production"
- PMID:27029000: "Macrophage infiltration was significantly elevated in the lung of KO mice."
- PMID:30820526: "accumulation of infiltrating neutrophils and increased production of pro-inflammatory cytokine genes compared with WT mice"
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Not novel: GOA carries this term on the horse AFAP1L2 product A0A3Q2HBW2 by IBA from PAINT node PTN002682769 and by Compara transfer. Human XB130 depletion reduces EGF-induced Akt and GSK3beta phosphorylation and growth factor-induced Src activation, supporting a positive contribution to signaling downstream of the EGF receptor through its Src and p85 docking roles. EGFR is one of several kinase inputs XB130 couples to PI3K, so the human review keeps the term as non-core. The horse model is inside the PAINT clade, justifying the transfer.
Supporting Evidence:
- PMID:17412687: "Down-regulation of endogenous XB130 with siRNA reduced c-Src activity, IL-8 production, EGF-induced phosphorylation of Akt and GSK3beta"
- file:interpro/panther/PTHR14338/PTHR14338-paint.tsv: "PTHR14338 PTN002682769 GO:0045742 P IBD"