The review combines 12 direct and 19 database assessments: 9 ACCEPT, 16 KEEP_AS_NON_CORE, 3 MODIFY, 1 TOO_GENERAL and 2 UNDECIDED. The 31 original source objects/order, nine original reference identities, four splice-product definitions and zero quotation paths remain unchanged. Four complete primary references are added, giving 13 references. No NEW annotation is introduced.
One core describes integrin binding at focal adhesions and its contribution to integrin activation and cell-matrix adhesion. The GO process pair is not redundant by strict is_a/part_of ancestry. Contextual skin, migration and signaling roles remain positive where supported, without expanding the core to every downstream phenotype. Direct actin binding and the specific nuclear-import step remain unresolved.
The precise evidence boundaries matter: tagged colocalization is not direct actin binding; nuclear abundance is not a kinetic import measurement; extracellular latent TGF-beta activation is distinct from production; and natural splice products are not interchangeable with artificial domain deletions. The three questions in the review address these remaining mechanistic/product uncertainties without asserting new functions.
The direct and database notes/guides are retained unchanged as component assessments. The integrated source guide explains their union. All 21 normal-source files are preserved, with no normalization or refetch. The genuine intake research-provider attempts failed (Falcon authorization failure and the permitted fallback quota/authentication failure); no provider report was manufactured. Credential-bearing raw traces remain private and were not inspected or included in the delivery.
Completion status is computed from actual validation. A completed review can contain explicit UNDECIDED assessments; status is not a claim that those biological uncertainties are resolved. No canonical publication or merge is implied by this private integration packet.
Kindlin-1 is an intracellular adhesion regulator whose best-supported mechanism connects beta-integrin cytoplasmic tails to integrin activation and matrix attachment. Human-cell experiments in PMID:14634021(../../../publications/PMID_14634021.md), Results and Figures 4–6 and 8–9, place endogenous kindlin-1 at focal adhesions and conditional membrane ruffles and recover it with integrin-tail constructs. Because the tail assay uses cell lysate, it establishes association without a purified binary affinity measurement. Kindlin-1 alone did not activate alphaIIbbeta3 in that experiment. The later PMID:19804783(../../../publications/PMID_19804783.md), integrin-activation and focal-adhesion-targeting Results and Figures 4–5, demonstrates cooperation with talin. Human functional constructs and mouse purified F0 structural domains are separate experiments; artificial F0 deletions are not natural splice products.
The endogenous human localization evidence is strongest in keratinocytes. PMID:18528435(../../../publications/PMID_18528435.md), confocal-localization Results and Figures 3a, 4 and 7a, distinguishes a diffuse cytoplasmic pool, vinculin-positive focal adhesions and basal skin enrichment. Co-immunoprecipitation in Figure 2 establishes cellular association with kindlin-2 and migfilin, without identifying a purified binary interaction. PMID:17012746(../../../publications/PMID_17012746.md), Figure 2C–D and corresponding Results, places immunogold intracellularly near the basal membrane between hemidesmosomes. This tissue assay resolves a cell-matrix junctional zone, not a specific focal adhesion or hemidesmosome component. The broader junction annotation therefore records an assay resolution limit, whereas the cultured-cell focal-adhesion experiments resolve a distinct, more specific location.
Loss-of-function evidence links these adhesion roles to epithelial behavior. In PMID:17012746(../../../publications/PMID_17012746.md), Figures 4–8 and their Results address proliferation, polarized membrane-protein distribution, attachment to fibronectin/laminin 332 and migration directionality. These phenotypes do not establish motor activity or cell-cycle catalysis. PMID:21356350(../../../publications/PMID_21356350.md), Figure 2A–B and 2D–F with the original Methods/Results, compares normal and Kindler-syndrome-derived keratinocytes with kindlin-2 depletion. Active beta1 integrin is normalized to total surface receptor; combined deficiency markedly impairs attachment, while single-deficient attachment differences are small and not significant. Kindlin-1 and kindlin-2 overlap in function but are not interchangeable. Cultured gap closure and directionality do not establish every stage of organismal wound healing.
Skin signaling adds context beyond the narrow adhesion mechanism. PMID:24681597(../../../publications/PMID_24681597.md), Results on latent TGF-beta activation and Wnt signaling, Figures 4–5 and the reporter/immunostaining Methods, separates mouse epidermal perturbation from corroborative human Kindler-syndrome skin observations. Alpha-v-beta-6-dependent activation of an extracellular latent TGF-beta pool concerns ligand availability, not demonstrated cytokine biosynthesis or secretion. The signaling-regulation replacement retains that positive biology. The seemingly closer GO:0036363 and GO:1901390 activation process terms were checked against official QuickGO on this date: both are obsolete, with comments that they represent molecular functions. They are not suitable replacement process terms. This check does not claim an exhaustive search of all possible active terms.
The same Wnt study reports increased nuclear beta-catenin/LEF1 and interprets it as nuclear translocation. It also changes Wnt ligand/receptor expression, shows rescue by manipulation of Wnt signaling and discusses beta-catenin stabilization and junctional sequestration. An import-regulation term does not require direct nuclear-pore binding or a particular kinetic assay. The open issue is how much of the changed steady-state nuclear pool reflects import versus export, retention or protein abundance. Full-text access permits that uncertainty to be assessed; it does not by itself settle the mechanism. The UNDECIDED transport annotation remains an explicit flag, alongside positive Wnt-regulatory evidence. A controlled transport/turnover time course would discriminate the alternatives.
Direct actin binding remains a separate question. PMID:16876785(../../../publications/PMID_16876785.md), original article in the author thesis, journal pages 3142–3151, Methods/Results and Figure 6 caption, shows tagged mouse kindlin-1 at adhesions and F-actin-associated structures. Colocalization cannot distinguish direct binding from recruitment through another adhesion protein. The historical 637-residue construct has not been sequence-remapped to the current 677-residue mouse record. This does not negate actin binding; purified-protein assays with sedimentation and aggregation controls are needed to test it directly.
Four natural human splice products are retained in the product map; their functions cannot be assigned from artificial deletion constructs, phosphorylation-state bands or unidentified residual immunostaining. The target-specific InterPro record identifies a kindlin/fermitin PH domain at residues 370–493, but that domain assignment alone does not demonstrate kindlin-1 lipid specificity or justify a second lipid-binding core function. Natural-product complementation and full-length/PH-domain lipid-binding experiments are recorded as testable questions and experiments. The direct and database guides document which original sections were actually recovered, and where figure pixels, supplements, sequence joins or phylogenetic paths remain unverified. No publication quotations are added.