FERMT1 encodes kindlin-1, an intracellular FERM-domain adhesion protein that binds beta-integrin cytoplasmic tails and cooperates with talin to promote integrin activation at focal adhesions. In keratinocytes, it supports attachment and spreading on extracellular matrix and contributes to epithelial polarity and migration. Context-dependent regulation of Wnt and TGF-beta signaling links kindlin-1 to skin homeostasis, hair-follicle cycling and stem-cell behavior. Most mechanistic evidence concerns full-length kindlin-1; shorter natural splice products alter its domain architecture.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001954 positive regulation of cell-matrix adhesion | IEA GO_REF:0000107 | ACCEPT | Summary: Kindlin-1 promotes integrin-dependent cell-matrix adhesion. Reason: The ortholog source in PMID:24681597 shows defective adhesion and spreading on alpha-v-beta-6-dependent substrates after mouse keratinocyte Fermt1 loss. Actual human kindlin-1 studies independently support integrin-tail association and matrix-dependent spreading (PMID:14634021) and cooperation with talin in integrin activation (PMID:19804783). This is a regulatory contribution to adhesion, not extracellular-matrix production. Retain the conserved core role without assigning the measured activity to all four natural splice products. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0005178 integrin binding | IBA GO_REF:0000033 | ACCEPT | Summary: Integrin binding is a core molecular function of kindlin-1. Reason: The inherited IBD assertion is biologically consistent with human kindlin-1 association with beta-integrin cytoplasmic tails in PMID:14634021. That experiment uses recombinant tails and a human-kindlin-containing cell lysate, so it is not described as an isolated two-purified-protein affinity measurement. Independent human functional constructs in PMID:19804783 support the integrin coactivation mechanism. Literal PAINT joins are verified; the unreturned tree/MSA is a provenance limit rather than evidence of target divergence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001043969 SUPPORTS TRANSFER Literal positive IBD term/node/donor identifiers match the accepted PTHR16160 PAINT TSV, and Q9BQL6 is an official family member. Target-to-node topology and MSA retrieval timed out and remain unverified; no loss or divergence is inferred from that access limitation. Donor count and target self-WITH are not criticisms. |
| GO:0005737 cytoplasm | IDA PMID:18528435 Colocalization of kindlin-1, kindlin-2, and migfilin at kera... | KEEP AS NON CORE | Summary: Kindlin-1 has a cytoplasmic pool in human keratinocytes. Reason: PMID:18528435 Results, confocal-localization section and Figure 3a show diffuse cytoplasmic kindlin-1 staining in normal human keratinocytes alongside vinculin-positive focal adhesions. Retain the observed broader pool as non-core rather than equating every cytoplasmic signal with an adhesion complex. Residual labeling in mutant or depleted cells and the unidentified approximately 65-kDa band do not establish a particular natural splice product. Supporting Evidence: |
| GO:0005829 cytosol | IDA PMID:17012746 Kindlin-1 is a phosphoprotein involved in regulation of pola... | KEEP AS NON CORE | Summary: The original immunogold evidence supports intracellular kindlin-1 adjacent to the basal plasma membrane. Reason: PMID:17012746 Results and Figure 2CβD place gold labeling inside normal human basal keratinocytes near the membrane facing the basement membrane, between hemidesmosomes. The cytosol definition includes particulate protein complexes outside organelles; it does not require a freely soluble fraction. Retain the curated cytosolic localization as non-core with this microscopy scope. The paper does not provide biochemical separation of a soluble cytosolic pool or imply an exclusive compartment. Supporting Evidence: |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Kindlin-1 associates with the actin-linked adhesion cytoskeleton. Reason: The Swiss-Prot subcellular-location mapping SL-0090 corresponds to the actual human UniProt cytoskeleton statement. Endogenous human HaCaT localization at focal adhesions and actin-fiber ends is documented in PMID:14634021. Keep this broad structural-location claim without converting colocalization into direct actin binding. The inspected strict ontology path query does not make focal adhesion GO:0005925 an is_a/part_of descendant of cytoskeleton GO:0005856, so a hierarchy-only TOO_GENERAL decision is not justified here. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0090 SUPPORTS TRANSFER SL-0090 is a curated UniProt subcellular-location mapping; it is not a Human Protein Atlas assay. |
| GO:0005925 focal adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Focal adhesions are a principal functional location of kindlin-1. Reason: The positive IBD has the exact GOA node and seeds, including human FERMT1 itself as expected. Endogenous human localization in PMID:14634021 and full-length human construct localization in PMID:19804783 independently support focal-adhesion residence. Artificial domain deletions in the latter study do not establish activities of the four natural splice products. No ancestry/MSA reconstruction is claimed from the literal TSV match. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002700591 SUPPORTS TRANSFER Literal positive IBD term/node/donor identifiers match the accepted PTHR16160 PAINT TSV, and Q9BQL6 is an official family member. Target-to-node topology and MSA retrieval timed out and remain unverified; no loss or divergence is inferred from that access limitation. Donor count and target self-WITH are not criticisms. |
| GO:0005925 focal adhesion | IDA PMID:18528435 Colocalization of kindlin-1, kindlin-2, and migfilin at kera... | ACCEPT | Summary: Kindlin-1 localizes to human keratinocyte focal adhesions. Reason: PMID:18528435 directly shows endogenous kindlin-1 colocalization with vinculin in normal human keratinocytes (Figure 3a). Tagged kindlin-1 and migfilin, with kindlin-2 immunostaining in HaCaT cells, provide corroborating focal-adhesion colocalization (Figure 4). This is a principal site of its adhesion-related activity. Cellular co-immunoprecipitation supports association, not purified pairwise binding or identity of every complex component. Supporting Evidence: |
| GO:0005925 focal adhesion | IEA GO_REF:0000120 | ACCEPT | Summary: Both curated location mapping and ortholog evidence support focal adhesions. Reason: This combined electronic source includes mouse P59113/Ensembl orthology and UniProt SL-0118 focal-adhesion mapping. The mouse donor has an IDA localization annotation from PMID:16876785, whose original tagged-protein microscopy was read. Actual endogenous human localization in PMID:14634021 and human full-length construct localization in PMID:19804783 independently corroborate the compartment. Preserve the combined-source identifiers and distinguish mouse donor assays from human corroboration. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Mouse P59113 has an independently grounded focal-adhesion IDA record; SL-0118 maps the human curated focal-adhesion statement. Other inferred donor rows are not used as the sole source chain. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Mouse P59113 has an independently grounded focal-adhesion IDA record; SL-0118 maps the human curated focal-adhesion statement. Other inferred donor rows are not used as the sole source chain. UniProtKB-SubCell:SL-0118 SUPPORTS TRANSFER Mouse P59113 has an independently grounded focal-adhesion IDA record; SL-0118 maps the human curated focal-adhesion statement. Other inferred donor rows are not used as the sole source chain. |
| GO:0007155 cell adhesion | IDA PMID:17012746 Kindlin-1 is a phosphoprotein involved in regulation of pola... | MODIFY | Summary: The measured adhesion phenotype concerns cell attachment to extracellular matrix. Reason: PMID:17012746 assays primary human control and Kindler-syndrome keratinocyte attachment to fibronectin and laminin 332; the deficient cells attach less efficiently (Figure 6D and adhesion Methods). GO:0007160 cell-matrix adhesion describes that observed function more precisely than generic cell adhesion. The intracellular adhesion-associated protein contributes to attachment; it is not itself an extracellular matrix ligand. Keep the original source term and evidence code unchanged. Proposed replacements: cell-matrix adhesion Supporting Evidence: |
| GO:0007155 cell adhesion | IGI PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce... | MODIFY | Summary: Kindlin-1 and kindlin-2 contribute overlapping support to cell-matrix adhesion. Reason: PMID:21356350 Figure 2B compares human keratinocyte lines lacking kindlin-1, depleted of kindlin-2, or deficient in both, on laminin 332 and fibronectin. Single-deficient adhesion is approximately 80β90% of control and not significantly different, whereas double deficiency strongly impairs attachment and spreading. The genetic-interaction context supports cell-matrix adhesion, GO:0007160, without attributing the whole double-deficient phenotype solely to FERMT1. Cell-cell-junction defects in this study are particularly associated with kindlin-2. Proposed replacements: cell-matrix adhesion Supporting Evidence: |
| GO:0007160 cell-matrix adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Kindlin-1 participates in integrin-mediated adhesion to extracellular matrix. Reason: The literal PTHR16160 IBD supports inherited cell-matrix adhesion, and actual human kindlin-1 loss reduces spreading on fibronectin in PMID:14634021. Human kindlin-1 functional constructs in PMID:19804783 cooperate with talin and localize to matrix-dependent focal adhesions. This is intracellular integrin regulation and adhesion-site organization, not adhesive extracellular-ligand activity. No new evolutionary placement is asserted beyond the recovered PAINT records. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001043969 SUPPORTS TRANSFER Literal positive IBD term/node/donor identifiers match the accepted PTHR16160 PAINT TSV, and Q9BQL6 is an official family member. Target-to-node topology and MSA retrieval timed out and remain unverified; no loss or divergence is inferred from that access limitation. Donor count and target self-WITH are not criticisms. |
| GO:0007229 integrin-mediated signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: The kindlin family/domain mapping is consistent with integrin signaling. Reason: The actual Q9BQL6 InterPro response maps the kindlin PH-domain entry IPR037837 to residues 370β493 and the kindlin-family entry IPR037843 to residues 3β676; both carry this GO mapping. Human integrin-tail association and the functional human full-length versus domain-deletion comparison in PMID:14634021 and PMID:19804783 support a kindlin contribution to integrin signaling. A domain match alone is not treated as an independent assay or a basis for transferring other paralogs' developmental functions. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR037837 SUPPORTS TRANSFER Both exact InterPro entries occur on the human target and map GO:0007229. Official family labels and target intervals were read; the biological corroboration is target-specific. InterPro:IPR037843 SUPPORTS TRANSFER Both exact InterPro entries occur on the human target and map GO:0007229. Official family labels and target intervals were read; the biological corroboration is target-specific. |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kindlin-1 restrains expression of a subset of Wnt-pathway genes in skin. Reason: PMID:24681597 reports altered Wnt-ligand/receptor expression after mouse Fermt1 loss and human Kindler-syndrome skin expression differences. Some genes change in opposite directions; the defensible negative-regulation claim concerns the subset elevated when kindlin-1 is absent. Retain the broad contextual annotation without claiming global transcriptional repression or direct DNA binding. This is separate from the core integrin-binding activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0030054 cell junction | IDA PMID:17012746 Kindlin-1 is a phosphoprotein involved in regulation of pola... | KEEP AS NON CORE | Summary: Kindlin-1 occurs at the basal epithelial cellβmatrix junction. Reason: PMID:17012746 Figure 2AβD and its Results localize kindlin-1 to the dermalβepidermal junction region, intracellularly at the basal membrane between hemidesmosomes. GO:0030054 includes cellβmatrix connections as well as cellβcell connections. Retain the positive junction annotation as non-core tissue context; it is not evidence that kindlin-1 is a hemidesmosome component or an adherens-junction component. Cultured focal adhesions are independently resolved in PMID:18528435, while the original skin localization is broader. The immunogold assay resolves the basal cell-matrix junctional zone between hemidesmosomes, but does not identify an individual focal adhesion in situ. That is the resolution ceiling of this tissue assay; the independently supported focal-adhesion term is not substituted for a location that this source did not resolve. |
| GO:0030335 positive regulation of cell migration | IEA GO_REF:0000117 | TOO GENERAL | Summary: The broad migration term is covered by the retained epidermal wound-spreading claim. Reason: Positive migration regulation is biologically supported, but the official strict ontology path establishes GO:1903691 positive regulation of wound healing, spreading of epidermal cells is_a GO:0030335. The direct-lane assessment retains the existing same-gene GO:1903691 row 29 as contextual evidence from PMID:21356350. TOO_GENERAL removes redundant broad term coverage, not the observed migration phenotype. ARBA00028907 genuinely outputs GO:0030335; its alternative FunFam/taxon conditions were inspected, but the exact target rule-condition satisfaction was not independently replayed. This decision requires row 29 to remain positive in integration. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00028907 SUPPORTS TRANSFER Actual ARBA00028907 consequent is GO:0030335. The strict typed narrower-term path is verified separately; no target-specific loss is alleged. |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kindlin-1 promotes local TGF-beta receptor signaling through ligand availability. Reason: PMID:24681597 shows that mouse kindlin-1 enables alpha-v-beta-6-dependent activation/release of latent matrix-associated TGF-beta1; Fermt1-deficient skin has reduced pSMAD2/3, and soluble ligand restores the cellular response. Human Kindler-syndrome skin also shows reduced pSMAD2/3. Retain the positive signaling-regulation inference as a skin-context function, without assigning TGF-beta synthesis, receptor kinase activity, or equivalent effects on every TGF-beta isoform. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0032587 ruffle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Kindlin-1 can redistribute to membrane ruffles under TGF-beta stimulation. Reason: SL-0301 maps the human UniProt ruffle-membrane statement. PMID:14634021 directly reports endogenous human HaCaT kindlin-1 enrichment in membrane ruffles after TGF-beta treatment, while some focal-adhesion staining remains. Preserve this conditional peripheral location, without treating it as an exclusive steady-state compartment or a transmembrane topology. The mapping is not an HPA-derived localization assay. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0301 SUPPORTS TRANSFER SL-0301 is the exact UniProt ruffle-membrane mapping; the stimulus-dependent human source observation was recovered. |
| GO:0033625 positive regulation of integrin activation | IGI PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce... | ACCEPT | Summary: Kindlin-1 promotes Ξ²1-integrin activation in human keratinocytes. Reason: PMID:21356350 Figure 2A measures the activation-sensitive 12G10 signal normalized to total surface Ξ²1 integrin detected by 4B7R. Activity falls to approximately 60% with kindlin-1 deficiency, 90% with kindlin-2 depletion and 20% with combined deficiency. This directly measured receptor-activation readout supports the positive-regulation annotation and partial compensation between kindlins. It is not a purified binary-binding experiment or proof of a universal effect on every integrin. Supporting Evidence: |
| GO:0033630 positive regulation of cell adhesion mediated by integrin | IEA GO_REF:0000107 | ACCEPT | Summary: Kindlin-1 promotes adhesion mediated by integrins. Reason: The mouse donor IMP in PMID:24681597 has a specific mechanistic basis: loss of kindlin-1 compromises alpha-v-beta-6-dependent attachment/spreading despite elevated integrin abundance. Human integrin-tail association and human construct/talin coactivation in PMID:14634021 and PMID:19804783 independently support conserved integrin regulation. Retain this core regulatory role, separating integrin activation from ligand synthesis and from conditional downstream skin phenotypes. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0042308 negative regulation of protein import into nucleus | IEA GO_REF:0000107 | UNDECIDED | Summary: The source establishes altered nuclear signaling-protein distribution, but the import-specific step is unresolved. Reason: The exact mouse donor IMP is recovered, and the full original PMID:24681597 Results and Figure 5 show increased nuclear beta-catenin/LEF1 after Fermt1 loss, with related observations in human Kindler-syndrome skin. The authors interpret this redistribution as nuclear translocation. GO:0042308 includes reducing the extent of cytoplasm-to-nucleus movement; it does not require a direct interaction with a nuclear pore or a particular kinetic assay. Nevertheless, the same study also changes Wnt ligand/receptor expression and discusses beta-catenin stabilization and junctional sequestration. Its steady-state nuclear staining does not resolve how altered import, export, retention and protein stability contribute. UNDECIDED explicitly flags this narrower mechanistic uncertainty after full-text access; it neither accepts the transport assertion nor declares it disproved or over-annotated. Retain the separately supported negative Wnt-signaling role (row 27). Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P59113 UNRESOLVED The donor IMP is recovered, but its nuclear-distribution evidence does not resolve the specific transport step in the target. ensembl:ENSMUSP00000047616 UNRESOLVED The donor IMP is recovered, but its nuclear-distribution evidence does not resolve the specific transport step in the target. |
| GO:0043616 keratinocyte proliferation | IDA PMID:17012746 Kindlin-1 is a phosphoprotein involved in regulation of pola... | KEEP AS NON CORE | Summary: Kindlin-1 supports normal keratinocyte proliferation in the studied human systems. Reason: PMID:17012746 shows reduced Ki67 labeling in affected epidermis (Figure 4CβD) and slower expansion of cultured kindlin-1-deficient keratinocytes (Figure 6C). These are positive tissue and cell-context findings. Retain the imported process as non-core downstream biology rather than treating necessity for population expansion as evidence that kindlin-1 directly executes DNA replication or cell-cycle chemistry. Cultured-cell apoptosis was not increased in the reported assay. Supporting Evidence: |
| GO:0051015 actin filament binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Direct binding to actin filaments is not resolved by the recovered donor localization assay. Reason: Mouse P59113 carries an IDA annotation from PMID:16876785. The complete original article recovered within the author thesis describes EGFP-kindlin-1 microscopy in mouse fibroblasts/keratinocytes and colocalization with focal adhesions and phalloidin-positive structures. The inspected original Methods, Results and Figure 6 caption do not establish a direct actin-binding measurement; localization within an actin-associated complex does not distinguish direct from indirect association. Retain source-specific uncertainty rather than negate actin binding or transfer a kindlin-2 assay. The historical mouse construct is described as 637 residues and has not been sequence-remapped to the current 677-residue donor. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P59113 UNRESOLVED The exact donor IDA record is present. The original article supports tagged localization/colocalization; direct F-actin binding and the historical construct sequence correspondence remain unresolved. ensembl:ENSMUSP00000047616 UNRESOLVED The exact donor IDA record is present. The original article supports tagged localization/colocalization; direct F-actin binding and the historical construct sequence correspondence remain unresolved. |
| GO:0051546 keratinocyte migration | IDA PMID:17012746 Kindlin-1 is a phosphoprotein involved in regulation of pola... | KEEP AS NON CORE | Summary: Kindlin-1 supports directed keratinocyte migration. Reason: PMID:17012746 Figure 7 and migration Methods compare human primary keratinocytes: deficient cells show slower monolayer closure, reduced velocity and less directed individual tracks. Figure 8 adds abnormal protrusion/retraction behavior. Retain the migration process as a contextual consequence of adhesion and cytoskeletal organization; this does not assign motor activity or generalize an in vitro closure assay to all stages of wound repair. Supporting Evidence: |
| GO:0051886 negative regulation of timing of anagen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kindlin-1 helps restrain premature hair-follicle anagen entry in mouse skin. Reason: PMID:24681597 reports premature entry into a subsequent anagen phase after epidermal Fermt1 deletion, following initially near-normal follicle morphogenesis/cycling. Wnt deregulation and rescue evidence support a role in cycle timing. Retain this specific mammalian skin-context orthology inference; it is not a demonstrated human intervention result or a constitutive inhibition of all follicle growth. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0071636 positive regulation of transforming growth factor beta production | IEA GO_REF:0000107 | MODIFY | Summary: The demonstrated effect is positive regulation of TGF-beta signaling through latent-ligand activation. Reason: The exact donor source PMID:24681597 measures alpha-v-beta-6-dependent release/activation of extracellular latent TGF-beta1 and downstream reporter/SMAD responses. The GO production branch concerns appearance through cytokine biosynthesis or secretion; activation of an already extracellular latent pool does not by itself establish that production step. Preserve the positive regulatory biology using GO:0030511, already represented by row 15, rather than create a new assertion. This is a role correction, not a strict ancestor refinement, and does not imply that TGF-beta production is biologically impossible. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P59113 SOURCE WEAK OR INFERRED The exact IMP donor is recovered. Its latent-ligand activation experiment supports signaling regulation but does not resolve cytokine biosynthesis or secretion. ensembl:ENSMUSP00000047616 SOURCE WEAK OR INFERRED The exact IMP donor is recovered. Its latent-ligand activation experiment supports signaling regulation but does not resolve cytokine biosynthesis or secretion. Proposed replacements: positive regulation of transforming growth factor beta receptor signaling pathway |
| GO:0071711 basement membrane organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kindlin-1 contributes to basement-membrane organization through epithelial adhesion. Reason: The mouse source PMID:24681597 reports basement-membrane splitting and dermalβepidermal separation following keratinocyte Fermt1 loss, with a related adhesion-defective beta1-integrin model supporting an integrin-dependent mechanism. Retain this tissue-context organizational role. Kindlin-1 is an intracellular adhesion regulator, not a basement-membrane structural constituent or collagen-synthesis enzyme; the donor phenotype is not relabeled as a direct assay of every human isoform. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0071944 cell periphery | IDA PMID:18528435 Colocalization of kindlin-1, kindlin-2, and migfilin at kera... | KEEP AS NON CORE | Summary: Kindlin-1 is enriched near the basal keratinocyte periphery in human skin. Reason: PMID:18528435 Results and Figure 7a describe strong staining near the cell periphery of basal keratinocytes in normal frozen skin, with weaker labeling elsewhere in the epidermis. Retain this tissue-level location as non-core context. It does not establish insertion into the lipid bilayer, and the broader in situ signal is not restricted to the cultured focal adhesions independently resolved in Figures 3β4. Supporting Evidence: |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kindlin-1 restrains canonical Wnt signaling in epidermal cells. Reason: PMID:24681597 combines mouse reporter responses, nuclear beta-catenin/LEF1 changes and rescue by kindlin-1 with human Kindler-syndrome skin observations. The integrin-binding-deficient kindlin-1 construct retains reporter rescue, separating this regulatory context from the core integrin-binding mechanism. Retain the negative Wnt-signaling inference without claiming a defined direct nuclear-import mechanism or equivalence of the artificial construct to any natural splice product. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
| GO:0090162 establishment of epithelial cell polarity | IDA PMID:17012746 Kindlin-1 is a phosphoprotein involved in regulation of pola... | KEEP AS NON CORE | Summary: Kindlin-1 contributes to normal epithelial polarity in human basal keratinocytes. Reason: PMID:17012746 Figure 5 shows abnormal distribution of collagen XVII and Ξ±6 integrin in kindlin-1-deficient skin, while Figure 6A shows multipolar cultured cells. This supports the curated polarity process in the epidermal context. Retain it as non-core organization downstream of the adhesion-associated protein; the experiments do not isolate a dedicated polarity-establishment reaction or prove that all epithelial tissues and splice products behave identically. Supporting Evidence: |
| GO:1903691 positive regulation of wound healing, spreading of epidermal cells | IGI PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce... | KEEP AS NON CORE | Summary: Kindlin-1 contributes to epithelial spreading and closure of a cultured wound gap. Reason: PMID:21356350 Figure 2DβF and the cell-migration Methods show delayed gap closure and reduced directional movement with kindlin-1 deficiency, with more severe defects after combined kindlin-1/kindlin-2 deficiency. Retain the existing spreading-related wound-healing annotation as non-core and explicitly limited to human keratinocyte monolayers. The assay combines motility, adhesion and population behavior; it does not separately establish every in vivo wound-healing phase or a FERMT1-exclusive effect. Supporting Evidence: |
| GO:2000647 negative regulation of stem cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Kindlin-1 restrains cutaneous stem-cell proliferation in the tested context. Reason: The mouse source PMID:24681597 reports expansion/proliferation of epidermal and hair-follicle stem-cell compartments after kindlin-1 loss, linked to altered Wnt/TGF-beta availability. This context differs from positive proliferation effects reported for other keratinocyte preparations; it is not a universal direction for all cells or developmental stages. Retain the bounded stem-cell regulatory inference as non-core, with human skin observations providing context rather than a matched human stem-cell intervention. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P59113 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. ensembl:ENSMUSP00000047616 SUPPORTS TRANSFER Actual mouse Fermt1 P59113 QuickGO record contains the matching IMP annotation from PMID:24681597; ENSMUSP00000047616 is the mouse 677-residue translation. Transfer is contextual orthology inference, not an experiment on every human splice product. |
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Download this section (compressed HTML)Q: Which molecular interactions account for the integrin-independent Wnt-regulatory effects of kindlin-1, and do they alter nuclear import specifically or other determinants of beta-catenin and LEF1 distribution?
Q: Which integrin-regulatory and localization activities are retained by the naturally shortened FERMT1 splice products, as distinct from artificial domain deletions and phosphorylation states?
Q: Does the observed association of kindlin-1 with F-actin reflect direct filament binding or an interaction mediated by other adhesion-complex components?
Q: Does the PH domain of kindlin-1 confer experimentally demonstrated lipid specificity and membrane recruitment in the intact protein, and how does this contribution interact with beta-integrin-tail binding?
Experiment: Test purified, sequence-verified full-length human kindlin-1 for saturable F-actin cosedimentation across protein and filament concentrations, with protein-alone sedimentation, aggregation, nonspecific-protein and positive binding controls; compare with an adhesion-complex reconstitution.
Hypothesis: Kindlin-1 association with F-actin may require another adhesion protein rather than direct filament binding.
Type: Biochemical binding and reconstitution
Experiment: Measure beta-catenin nuclear entry and exit over time in isogenic FERMT1-deficient and rescued human keratinocytes while controlling Wnt ligand exposure, total beta-catenin abundance, degradation and junctional sequestration; compare wild-type kindlin-1 with a sequence-verified integrin-binding-deficient construct.
Hypothesis: The altered nuclear beta-catenin pool may arise from changed signaling and stability without a specific change in the nuclear-import step.
Type: Live-cell transport and protein-turnover analysis
Experiment: Express each of the four sequence-verified natural FERMT1 splice products at matched levels in FERMT1-deficient keratinocytes and quantify focal-adhesion localization, surface-normalized integrin activation and matrix attachment, with wild-type rescue and empty-vector controls.
Hypothesis: Naturally shortened products may differ in localization or integrin regulation; artificial domain deletions do not establish those differences.
Type: Natural splice-product complementation
Experiment: Measure lipid binding of purified full-length human kindlin-1 and its PH domain using composition-controlled liposomes, then test structure-guided mutants for membrane recruitment and integrin activation in keratinocytes; verify folding, expression and beta-integrin-tail binding independently.
Hypothesis: Kindlin-1 lipid recognition may help position the integrin-binding machinery, but PH-domain membership alone does not establish lipid selectivity or an independent core activity.
Type: Lipid-binding biochemistry and cellular complementation
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