AFAP1L2: paired human–horse review notes

Biological evidence

The primary XB130 study establishes a signaling adaptor that activates Src and links EGF to downstream signaling and gene expression. It reports interaction motifs, kinase activation, knockdown effects and transcriptional reporters. The evidence supports specific kinase/adaptor roles rather than generic binding.

• PMID:17412687: XB130, a novel adaptor protein for signal transduction. — abstract cached; full-text availability must be checked separately.

Exact horse model

The full human818-residue sequence aligns to the horse850-residue model at88.6% identity. This supports the conserved adaptor mechanism and broad downstream cytokine/signaling claims. The cached abstract establishes IL-8; the separate DOI-linked full-paper excerpt documents the IL-6 result. Neither the Edison narrative nor ARBA is used as independent validation.

The reproducible alignment, source paths and hashes are in the paired comparison. Current UniProt sequences have not been proven identical to the original ProtNLM input sequences. Sequence anomalies are therefore recorded as model/transfer limitations, not as proven wrong-input pipeline errors.

Evidence gaps

The source excerpt file preserves the IL-6 sentence and full-paper URL because the publication cache is abstract-only. Consider tissue/condition-specific assays before treating cytokine phenotypes as universal horse physiology.

Review scope and checks

Every seeded annotation receives a current assessment. UNDECIDED marks unresolved source-specific or biological evidence; these are initial reviews rather than a claim that every original experimental assay has been independently reproduced or verified. The human Edison report is retained as a research synthesis and source-finding aid; decisive YAML excerpts cite primary publications, source records or reproducible analysis. The validator advisory to cite the deep-research file is deliberately not satisfied by citing AI prose as biological proof.

2026-10-20 — Full re-review, independent of the ProtNLM2 predictions

ProtNLM2 output was not opened or used. Sources: cached publications, UniProt record, PANTHER/PAINT files, falcon deep research (used only to find primary papers; no claim rests on it).

Identity

• Q8N4X5 is the reviewed, canonical 818-aa human AFAP1L2/XB130 (isoform 1 displayed; 4 isoforms). It is not a fragment or alternative gene model. Domains: N-terminal SH2/SH3-binding motif region, PH domains 175-271 and 353-447, coiled coil 652-749 (UniProt FT).
• PANTHER PTHR14338:SF4 (ACTIN FILAMENT-ASSOCIATED PROTEIN 1-LIKE 2). This is the 1:1 AFAP1L2 ortholog subfamily, separate from AFAP1 (SF8) and AFAP1L1 (SF1). Mouse Afap1l2 Q5DTU0 and the rat Afap1l2 gene products (UniProt REST: A0A8I5ZSJ9, F1M5W8, etc.) are also SF4. PTHR14338:SF9 has the same name but contains no members in the cached inventory.
• PAINT (interpro/panther/PTHR14338/PTHR14338-paint.tsv): PTN001023816 (Deuterostomia) has cytosol. PTN002682769 (Euteleostomi, AFAP1L2 clade) has GO:0030296, 0006954, 0007346, 0045742 and 0045893. Human Q8N4X5 is the only seed for every term. The curators did NOT propagate SH2/SH3 domain binding or the IL-6/IL-8 terms, and I take that as deliberate.

Key primary evidence

• PMID:17412687 Src binding and activation; knockdown reduces Src activity, IL-8, EGF-Akt and cell cycle.
• PMID:19060924 This is the core adaptor mechanism, with Akt selectivity (ERK unaffected).
• PMID:22496359 Independent rat ortholog evidence (SF4).
• PMID:26446840 Plus Src Y416, p85, Akt and G1 effects of knockdown.
• PMID:21084565
• PMID:27462298 Mouse construct (NM_001177796). The region is conserved in human per their Fig 2C, and it is distinct from the AFAP1/AFAP1L1 ABD.
• PMID:34470464 Mouse KO gives congenital hypothyroidism.

Changes vs previous review

• Inflammatory response (IBA+IDA): KEEP_AS_NON_CORE changed to MARK_AS_OVER_ANNOTATED. The evidence is a cell-line cytokine readout, already covered by the IL-6/IL-8 production rows.
• Positive regulation of DNA-templated transcription (IBA+IDA): KEEP_AS_NON_CORE changed to MARK_AS_OVER_ANNOTATED. The evidence is a reporter readout for a cytoplasmic adaptor.
• Positive regulation of EGFR signaling (IBA+IDA): ACCEPT changed to KEEP_AS_NON_CORE. EGFR is one of several upstream inputs.
• Cytoplasm, cytosol, SH2/SH3 domain binding and PTK activator activity stay ACCEPT. Cell cycle and IL-6/IL-8 stay KEEP_AS_NON_CORE. Support now adds PMID:19060924 and PMID:26446840.
• NEW: GO:0036312 PI3K regulatory subunit binding (IPI, PMID:19060924); GO:0051897 positive regulation of PI3K/PKB signal transduction (IMP; participation as the p85 docking scaffold; comparator check: human IRS1 and GAB1 carry it in QuickGO); GO:0051015 actin filament binding (ISS from mouse SF4 ortholog); GO:0030027 lamellipodium (IDA); GO:0016324 apical plasma membrane (ISS, mouse SF4 ortholog).
• Not proposed (necessity, not participation): thyroid hormone generation, thyroid follicle/folliculogenesis, cell migration, endocytosis, T-cell survival (Canale 2023) and mitophagy (Ma 2024, HCC). These are recorded here only.
• Status set to COMPLETE; core functions rewritten (p85 adaptor/PI3K-Akt; Src activator; actin scaffold).

Family/module checks

• interpro/panther/PTHR14338/PTHR14338-review.yaml places Q8N4X5 in SF4, which agrees with UniProt. It has no term assessments, so there is no conflict with these actions.
• No module in modules/ lists AFAP1L2/XB130.