Affinage

KANK2

KN motif and ankyrin repeat domain-containing protein 2 · UniProt Q63ZY3

Length
851 aa
Mass
91.2 kDa
Annotated
2026-06-10
14 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KANK2 is a scaffold protein of integrin adhesion complexes that couples adhesions to the microtubule cytoskeleton and tunes the mechanical link between integrins and actomyosin (PMID:27548916, PMID:32195252). It accumulates at the lateral border of focal adhesions and in central sliding adhesions, where its N-terminal KN motif directly binds the talin rod domain to activate talin and integrins while diminishing the talin–actomyosin linkage, thereby lowering force transmission across integrins and promoting central adhesion sliding (PMID:27548916). Its C-terminal ankyrin repeat domain directly engages a short helical KIF21A peptide at two distinct pockets, as resolved by crystallography, recruiting the cortical microtubule stabilization complex to adhesions and controlling microtubule dynamics and cell migration (PMID:29183992, PMID:32195252). In integrin αVβ5-dependent cells KANK2 acts preferentially through talin2 to regulate actin–microtubule crosstalk and drug sensitivity, while in mixed-adhesion contexts it engages talin1 for focal adhesion integrity and talin2 for dynamics and additionally links α5β1 fibrillar adhesions to stabilized microtubules (PMID:37460977, PMID:41776630). A nephrotic-syndrome–associated mutation (S684F) creates a gain-of-binding site for eIF4A1 that competitively displaces KIF21A and abolishes the ability of KANK2 to rescue focal adhesion structure in knockout podocytes, converting a gain of binding into functional loss (PMID:34274317). Independent of its adhesion role, KANK2 sequesters steroid receptor coactivators SRC-2 and SRC-3 in the cytoplasm to limit vitamin D receptor–driven transactivation (PMID:24671081), and physically interacts with HSP70 to reduce AIF release and apoptosis in epithelial cells (PMID:35327602).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 Medium

    Established a first molecular function for KANK2 by showing it retains transcriptional coactivators in the cytoplasm, with a disease mutation releasing them to the nucleus.

    Evidence Immunofluorescence of SRC-2/SRC-3 and vitamin D transactivation assays in patient vs. control keratinocytes, plus exome sequencing of the causative p.Ala670Val mutation

    PMID:24671081

    Open questions at the time
    • Direct physical SRC-2/3–KANK2 binding interface not mapped
    • Connection to the adhesion/microtubule role of KANK2 unestablished
    • Single patient lineage
  2. 2016 High

    Defined the core adhesion mechanism: KANK2 binds the talin rod via its KN motif to activate integrins while uncoupling talin from actomyosin, reducing integrin tension.

    Evidence Co-IP/pulldown mapping the KN motif–talin rod interaction, FRET integrin tension sensors, live-cell imaging and KN-motif mutagenesis across cell types

    PMID:27548916

    Open questions at the time
    • Talin isoform preference not resolved in this study
    • Quantitative contribution to migration left for later work
  3. 2017 High

    Resolved the structural basis for microtubule coupling, showing how the KANK2 ankyrin domain captures a KIF21A peptide at two pockets.

    Evidence Crystal structures of the KANK2 ankyrin domain–KIF21A peptide complex with site-directed mutagenesis and biochemical binding assays

    PMID:29183992

    Open questions at the time
    • Cellular consequences of disrupting the interface not tested here
    • Whether the two pockets bind cooperatively unaddressed
  4. 2020 Medium

    Placed KANK2 functionally within αVβ5 integrin adhesion complexes as the link to microtubules controlling drug sensitivity and migration.

    Evidence Mass spectrometry of isolated integrin adhesion complexes and siRNA knockdown with paclitaxel/vincristine sensitivity and migration assays

    PMID:32195252

    Open questions at the time
    • Talin isoform mediating the link not identified
    • Mechanism connecting microtubule stabilization to drug sensitivity unresolved
  5. 2021 High

    Explained how a nephrotic-syndrome mutation acts: S684F gains an eIF4A1-binding site that competitively displaces KIF21A, producing functional loss of adhesion rescue.

    Evidence Crystal structure of KANK2(S684F)–eIF4A1, competitive binding assays, and rescue experiments in KANK2-knockout mouse podocytes

    PMID:34274317

    Open questions at the time
    • Physiological role, if any, of eIF4A1 in wild-type podocytes unclear
    • In vivo kidney phenotype of the mutation not established in this study
  6. 2022 Medium

    Identified an anti-apoptotic role through HSP70, distinct from adhesion signaling.

    Evidence Reciprocal Co-IP of HSP70–KANK2, siRNA knockdown, hsp70.1 deletion in CLP mice, TUNEL staining and AIF release assays

    PMID:35327602

    Open questions at the time
    • KANK2 domain mediating HSP70 binding not mapped
    • Mechanistic link between KANK2 and AIF retention unresolved
  7. 2023 Medium

    Demonstrated talin isoform specificity, showing KANK2 acts through talin2 in αVβ5-reliant melanoma cells where KANK1 is dispensable.

    Evidence Talin1/talin2/KANK1/KANK2 siRNA, live-cell MT dynamics imaging, paclitaxel sensitivity and Transwell migration assays with adhesion-complex Western blots

    PMID:37460977

    Open questions at the time
    • Generality across non-αVβ5 cell types untested in this study
    • Direct talin2 binding interface not re-mapped
  8. 2024 Medium

    Identified upstream transcriptional control of KANK2 expression governing actin cytoskeleton integrity.

    Evidence EMSA and ChIP for E2F1, TFAP2C and NRF1 binding to the KANK2 promoter plus siRNA knockdown with F-actin readouts in renal tubular epithelial cells

    PMID:38253280

    Open questions at the time
    • Signals regulating these transcription factors on KANK2 unknown
    • Direct vs. indirect cytoskeletal effects of TF knockdown not separated
  9. 2026 Medium

    Extended the model to fibrillar adhesions and dual talin engagement, showing KANK2 links both αVβ5 focal adhesions and α5β1 fibrillar adhesions to stabilized microtubules.

    Evidence siRNA knockdown, MS of isolated adhesion complexes, proximity ligation assays, live-cell imaging, migration and paclitaxel sensitivity assays in RPMI-7951 cells

    PMID:41776630

    Open questions at the time
    • Structural basis for talin1 vs. talin2 selectivity not resolved
    • How a single KN motif partitions between adhesion types unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KANK2's distinct activities—talin/integrin scaffolding, coactivator sequestration, and HSP70/AIF-dependent apoptosis suppression—are integrated within a single cell remains unresolved.
  • No unifying study connecting the adhesion and non-adhesion roles
  • Regulation governing which interaction dominates in a given context unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0140313 molecular sequestering activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 1
Partners
EIF4A1HSPA1AKIF21ANCOA2NCOA3TLN1TLN2
Complex memberships
cortical microtubule stabilization complex (CMSC)integrin αVβ5 adhesion complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 KANK2 (and other Kank family members) accumulate at the lateral border of focal adhesions (FA belt) and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif, inducing talin and integrin activation while diminishing the talin-actomyosin linkage, thereby reducing force transmission across integrins and promoting central adhesion formation and sliding. Co-IP/pulldown identifying KN motif–talin rod interaction, FRET-based tension sensors across integrins, live-cell imaging of adhesion dynamics, mutagenesis of KN motif Nature cell biology High 27548916
2014 KANK2 (SIP) sequesters steroid receptor coactivators (SRC-2 and SRC-3) in the cytoplasm; a missense mutation (p.Ala670Val) abolishes this sequestering activity, causing SRC-2 and SRC-3 to mislocalize to the nucleus of epidermal basal cells, increasing vitamin D receptor-driven transactivation in patient keratinocytes. Immunofluorescence localization of SRC-2/SRC-3 in patient vs. control keratinocytes; vitamin D-induced transactivation assays in patient cells; whole-exome sequencing identifying causative mutation Journal of medical genetics Medium 24671081
2017 The C-terminal ankyrin repeat domain of KANK2 directly binds a ~22 amino acid stretch of KIF21A, adopting a helical conformation at two distinct pockets of the ankyrin domain, as revealed by crystal structures of the KANK2 ankyrin domain–KIF21A peptide complex, validated by site-directed mutagenesis. Crystal structure determination, site-directed mutagenesis, biochemical binding assays The Journal of biological chemistry High 29183992
2020 KANK2 is a key component of integrin αVβ5 integrin adhesion complexes linking them to microtubules via the cortical microtubule stabilization complex (CMSC); KANK2 knockdown mimics integrin αV knockdown by increasing sensitivity to microtubule poisons (paclitaxel, vincristine) and decreasing cell migration. Mass spectrometry-based proteomics of isolated integrin adhesion complexes; siRNA knockdown with drug sensitivity and migration assays Frontiers in cell and developmental biology Medium 32195252
2021 An NS-associated KANK2 mutation (S684F) creates a gain-of-binding interaction with eIF4A1 at the same site used by KIF21A; eIF4A1 competitively displaces KIF21A from the S684F mutant, and the mutant fails to rescue focal adhesion structure or cell adhesion in KANK2-knockout podocytes, converting a gain-of-binding mutation into a functional loss-of-function. Crystal structure of KANK2(S684F)–eIF4A1 complex; competitive binding assays; KANK2 knockout in mouse podocytes with rescue experiments; immunofluorescence of focal adhesions The Journal of biological chemistry High 34274317
2022 HSP70 physically interacts with KANK2; this interaction reduces AIF release and apoptosis in lung epithelial cells; KANK2 knockdown in epithelial cells aggravates apoptosis and tissue damage, while HSP70 treatment reverses cell death in a KANK2-dependent manner. Co-immunoprecipitation of HSP70–KANK2 complex; siRNA knockdown of KANK2; hsp70.1 gene deletion in CLP mice; TUNEL staining; AIF release assay Biomolecules Medium 35327602
2023 In MDA-MB-435S melanoma cells (which rely on integrin αVβ5), KANK2 specifically interacts with talin2 (not talin1) within focal adhesions; talin2 knockdown phenocopies KANK2 knockdown, perturbing actin–MT crosstalk (increased MT growth velocity), increasing paclitaxel sensitivity, and reducing cell migration, whereas KANK1 knockdown has none of these effects. siRNA knockdown of talin1, talin2, KANK1, or KANK2; live-cell imaging of MT dynamics; paclitaxel sensitivity assay; Transwell migration assay; Western blot of isolated integrin adhesion complexes Cellular & molecular biology letters Medium 37460977
2010 KANK2 (ankrd25) protein is localized to podocyte foot processes in mouse kidney, as determined by immunohistochemistry with a polyclonal antibody. Immunohistochemistry; RT-PCR for tissue expression Nephron. Experimental nephrology Low 20720434
2024 Transcription factors E2F1, TFAP2C, and NRF1 bind the upstream promoter of KANK2 to transactivate its expression in renal tubular epithelial cells; knockdown of any of these factors reduces KANK2 expression, deforms the actin cytoskeleton, and decreases F-actin content. EMSA and ChIP assays for transcription factor binding; siRNA knockdown of transcription factors with F-actin and cytoskeleton readouts; promoter mapping Experimental cell research Medium 38253280
2026 In RPMI-7951 melanoma cells, KANK2 is present in both integrin αVβ5 focal adhesions (FAs) and integrin α5β1 fibrillar adhesions (FBs); at FAs it functionally interacts with talin1 to maintain FA integrity and with talin2 to regulate FA dynamics; at FBs, KANK2 knockdown mimics integrin α5 knockdown by increasing microtubule-dependent cell migration, indicating KANK2 links FBs to microtubules and stabilizes them. siRNA knockdown; mass spectrometry of isolated integrin adhesion complexes; proximity ligation assay; live-cell imaging; Transwell migration assay; paclitaxel sensitivity assay Cell communication and signaling : CCS Medium 41776630

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation. Nature cell biology 133 27548916
2014 Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair. Journal of medical genetics 33 24671081
2020 KANK2 Links αVβ5 Focal Adhesions to Microtubules and Regulates Sensitivity to Microtubule Poisons and Cell Migration. Frontiers in cell and developmental biology 28 32195252
2022 HSP70 Ameliorates Septic Lung Injury via Inhibition of Apoptosis by Interacting with KANK2. Biomolecules 26 35327602
2023 Talin2 and KANK2 functionally interact to regulate microtubule dynamics, paclitaxel sensitivity and cell migration in the MDA-MB-435S melanoma cell line. Cellular & molecular biology letters 15 37460977
2017 Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins. The Journal of biological chemistry 15 29183992
2023 Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nature communications 13 37919278
2020 Therapeutic effects of KANK2 in myocardial infarction rats might be associated with the NF-κB p65 inhibition. International immunopharmacology 9 32570033
2021 Nephrotic-syndrome-associated mutation of KANK2 induces pathologic binding competition with physiological interactor KIF21A. The Journal of biological chemistry 5 34274317
2025 Pan-Cancer Analysis of KANK2: Clinical and Molecular Insights into Tumor Progression and Therapeutic Implications. Journal of Cancer 2 39895803
2010 Expression of novel podocyte-associated proteins sult1b1 and ankrd25. Nephron. Experimental nephrology 2 20720434
2024 Transcriptional mechanism of E2F1/TFAP2C/NRF1 in regulating KANK2 gene in nephrotic syndrome. Experimental cell research 1 38253280
2026 KANK2 at focal adhesions regulates their maintenance and dynamics, while at fibrillar adhesions it influences cell migration via microtubule-dependent mechanism. Cell communication and signaling : CCS 0 41776630
2026 Regulation of reticular adhesions by KANK2 and talin2 in two melanoma cell lines. Cell communication and signaling : CCS 0 42032724

Missed literature

Know a paper Affinage missed for KANK2? Flag it for the maintainers and the community.

No submissions yet.