{"gene":"KANK2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2016,"finding":"KANK2 directly binds the talin rod domain through its KN motif, accumulates at the lateral border of focal adhesions (FA belt) and in central sliding adhesions, activates talin and integrins, and diminishes the talin-actomyosin linkage, thereby reducing force transmission across integrins, inducing central adhesion formation and sliding, and decreasing cell migration speed.","method":"Co-IP, pulldown assays, FRAP, traction force microscopy, live-cell imaging, siRNA knockdown with phenotypic readouts in migration and adhesion","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding assays, force microscopy, live imaging, KO/KD) with strong mechanistic resolution in a single study","pmids":["27548916"],"is_preprint":false},{"year":2014,"finding":"A missense mutation (p.Ala670Val) in KANK2, which encodes the SRC-interacting protein (SIP), abolishes its ability to sequester steroid receptor coactivators (SRC-2 and SRC-3) in the cytoplasm; in patient keratinocytes, SRC-2 and SRC-3 relocalize to the nucleus of epidermal basal cells and vitamin D-induced transactivation is increased, causing palmoplantar keratoderma and woolly hair.","method":"Whole-exome sequencing, immunofluorescence localization of SRC coactivators, functional transactivation assay in patient-derived keratinocytes","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — patient mutation functionally validated by coactivator localization and transactivation assay, linking KANK2 to cytoplasmic sequestration of SRCs","pmids":["24671081"],"is_preprint":false},{"year":2007,"finding":"KANK2/SIP (SRC-Interacting Protein), an ankyrin-repeat containing protein, sequesters steroid receptor coactivators (SRCs) in the cytoplasm; estrogen-induced phosphorylation of SIP's PEST domain by casein kinase II causes dissociation of SRCs from SIP and their nuclear translocation, enabling gene coactivation.","method":"Co-IP, gain- and loss-of-function experiments, subcellular fractionation, kinase assays, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple functional readouts, phosphorylation mechanism defined by kinase assay and mutagenesis","pmids":["17476305"],"is_preprint":false},{"year":2012,"finding":"KANK2/SIP interacts directly with apoptosis-inducing factor (AIF) in mitochondria and inhibits caspase-independent, AIF-dependent apoptosis; apoptotic stimuli lead to rapid degradation of SIP, liberating AIF to translocate to the nucleus.","method":"Co-IP, subcellular fractionation, overexpression and knockdown with apoptosis assays, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct interaction demonstrated by Co-IP, functional consequence confirmed by gain/loss-of-function with specific apoptotic readouts","pmids":["22371500"],"is_preprint":false},{"year":2020,"finding":"KANK2 is a key component of integrin αVβ5 integrin adhesion complexes that links these adhesions to microtubules via the cortical microtubule stabilization complex (CMSC); KANK2 knockdown increases sensitivity to microtubule poisons (paclitaxel and vincristine) and decreases cell migration, mimicking integrin αV knockdown.","method":"Mass spectrometry-based proteomics of isolated integrin adhesion complexes, siRNA knockdown, cell migration assays, drug sensitivity assays","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — MS-based identification of KANK2 in αVβ5 IACs, validated by knockdown with specific phenotypic readouts","pmids":["32195252"],"is_preprint":false},{"year":2017,"finding":"Both KANK1 and KANK2 ankyrin domains bind a ~22 amino acid stretch of KIF21A; crystal structures of KIF21A peptide with KANK1 ankyrin domain and with KANK2 ankyrin domain show KIF21A is recognized by two distinct pockets and adopts helical conformations upon binding.","method":"Crystal structure determination, site-directed mutagenesis, biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with mutagenesis validation for both KANK1 and KANK2 complexes","pmids":["29183992"],"is_preprint":false},{"year":2022,"finding":"HSP70 physically interacts with KANK2; this interaction inhibits apoptosis-inducing factor (AIF) release and apoptosis in septic lung injury; knockdown of KANK2 aggravates apoptosis and tissue damage, while HSP70 treatment reverses these effects.","method":"Co-IP, siRNA knockdown, mouse CLP model, LPS-treated human alveolar epithelial cells, apoptosis assays","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo/in vitro KO with functional readout, but from a single lab","pmids":["35327602"],"is_preprint":false},{"year":2023,"finding":"KANK2 functionally interacts specifically with talin2 (not talin1) within integrin αVβ5 focal adhesions; talin2 knockdown mimics KANK2 knockdown by increasing microtubule growth velocity, increasing sensitivity to paclitaxel, and reducing cell migration.","method":"siRNA knockdown of talin1, talin2, KANK1, KANK2; isolation of integrin adhesion complexes; live-cell confocal imaging of microtubule dynamics; migration assays","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis-like genetic approach with multiple orthogonal readouts, single lab","pmids":["37460977"],"is_preprint":false}],"current_model":"KANK2 is an ankyrin-repeat scaffold protein that localizes to the lateral border of focal adhesions (FA belt) and central adhesions, where it directly binds the talin rod domain (via its KN motif) and KIF21A (via its ankyrin domain) to link integrin αVβ5 adhesion complexes to microtubules through the cortical microtubule stabilization complex; by activating talin/integrins while simultaneously weakening the talin-actomyosin linkage, KANK2 reduces integrin-ligand bond strength and regulates cell migration speed; additionally, KANK2 sequesters steroid receptor coactivators (SRCs) in the cytoplasm (a function disrupted by casein kinase II phosphorylation downstream of estrogen signaling, or by disease-causing mutations causing keratoderma/woolly hair), and interacts with AIF in mitochondria to suppress caspase-independent apoptosis."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing KANK2 as a cytoplasmic anchor for steroid receptor coactivators resolved how SRCs are retained outside the nucleus and revealed that estrogen signaling releases them via casein kinase II phosphorylation of KANK2's PEST domain.","evidence":"Co-IP, subcellular fractionation, kinase assays, and gain/loss-of-function experiments in cultured cells","pmids":["17476305"],"confidence":"High","gaps":["Whether KANK2-SRC sequestration operates in all steroid hormone pathways or is estrogen-specific","Structural basis of SRC recognition by KANK2","In vivo physiological significance of this sequestration mechanism"]},{"year":2012,"claim":"Demonstrating that KANK2 directly binds AIF in mitochondria and suppresses caspase-independent apoptosis revealed a second, compartmentally distinct function for the scaffold and showed that apoptotic stimuli liberate AIF by degrading KANK2.","evidence":"Co-IP, subcellular fractionation, overexpression and knockdown with apoptosis readouts","pmids":["22371500"],"confidence":"High","gaps":["The protease or pathway responsible for KANK2 degradation upon apoptotic stimuli","Whether KANK2's adhesion and mitochondrial pools are independently regulated","Structural details of the KANK2–AIF interaction"]},{"year":2014,"claim":"Identification of a causative KANK2 missense mutation in palmoplantar keratoderma/woolly hair families connected the SRC-sequestration mechanism to human disease and showed the mutation specifically disrupts cytoplasmic retention of SRC-2/SRC-3 in epidermal basal cells.","evidence":"Whole-exome sequencing, immunofluorescence of SRC coactivators, and transactivation assays in patient-derived keratinocytes","pmids":["24671081"],"confidence":"High","gaps":["Which downstream transcriptional programs are deregulated in affected keratinocytes","Whether other KANK2 functions (adhesion, apoptosis) contribute to the skin phenotype"]},{"year":2016,"claim":"Defining KANK2 as a talin-binding protein that localizes to the FA belt and central adhesions established its role as a mechanical regulator: it activates talin/integrins while uncoupling the talin-actomyosin linkage, reducing force transmission and controlling migration speed.","evidence":"Co-IP, pulldown, FRAP, traction force microscopy, live-cell imaging, and siRNA knockdown in migrating cells","pmids":["27548916"],"confidence":"High","gaps":["How KANK2 simultaneously activates talin yet weakens its F-actin linkage at the structural level","Whether KANK2's adhesion role and SRC-sequestration role are coupled or fully independent"]},{"year":2017,"claim":"Crystal structures of the KANK2 ankyrin domain bound to a KIF21A peptide revealed the atomic basis for microtubule-motor recruitment to adhesion sites, showing KIF21A is recognized by two distinct pockets and adopts helical conformations upon binding.","evidence":"X-ray crystallography with site-directed mutagenesis and biochemical binding assays","pmids":["29183992"],"confidence":"High","gaps":["How KANK2 coordinates simultaneous binding of KIF21A and other ankyrin-domain partners","Whether KANK1 and KANK2 compete for KIF21A at adhesion sites in vivo"]},{"year":2020,"claim":"Proteomic identification of KANK2 as a component of integrin αVβ5 adhesion complexes linked to the cortical microtubule stabilization complex clarified why KANK2 loss increases sensitivity to microtubule poisons and reduces migration.","evidence":"Mass spectrometry of isolated integrin adhesion complexes, siRNA knockdown, drug sensitivity and migration assays","pmids":["32195252"],"confidence":"High","gaps":["Whether KANK2 functions at other integrin heterodimer complexes beyond αVβ5","The full composition of the KANK2-containing CMSC at αVβ5 adhesions"]},{"year":2022,"claim":"Showing that HSP70 physically interacts with KANK2 and stabilizes its anti-apoptotic function in septic lung injury extended the AIF-sequestration model by identifying an upstream regulator that protects KANK2 from degradation.","evidence":"Co-IP, siRNA knockdown, mouse CLP sepsis model, LPS-treated human alveolar epithelial cells","pmids":["35327602"],"confidence":"Medium","gaps":["Single-lab finding; independent replication needed","Whether HSP70 stabilizes KANK2 protein levels or modulates the KANK2–AIF interaction directly","Relevance to non-pulmonary tissues"]},{"year":2023,"claim":"Demonstrating that KANK2 functionally partners with talin2 (not talin1) at αVβ5 adhesions refined the molecular specificity of KANK2's adhesion-microtubule coupling and explained isoform-specific phenotypes in microtubule dynamics and drug sensitivity.","evidence":"Selective siRNA knockdown of talin1/2 and KANK1/2, integrin adhesion complex isolation, live-cell confocal imaging of microtubule dynamics, migration assays","pmids":["37460977"],"confidence":"Medium","gaps":["Single-lab finding; structural basis for talin2 selectivity over talin1 not resolved","Whether talin2 preference holds in all cell types and integrin contexts"]},{"year":null,"claim":"How KANK2's three major functions—focal adhesion mechanotransduction, SRC coactivator sequestration, and mitochondrial AIF regulation—are coordinated within a single cell, and whether distinct KANK2 pools are independently regulated, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study has simultaneously measured adhesion, transcriptional, and apoptotic outputs of KANK2","Post-translational regulation beyond CKII phosphorylation is poorly characterized","In vivo knockout phenotypes in mammalian models have not been systematically described"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4]}],"complexes":["Cortical microtubule stabilization complex (CMSC)","Integrin αVβ5 adhesion complex"],"partners":["TLN2","KIF21A","AIFM1","NCOA2","NCOA3","HSPA1A","TLN1"],"other_free_text":[]},"mechanistic_narrative":"KANK2 is an ankyrin-repeat scaffold protein that coordinates integrin adhesion dynamics, microtubule capture, and transcriptional coactivator localization. At focal adhesions, KANK2 binds the talin rod domain via its KN motif—specifically partnering with talin2 at integrin αVβ5 adhesion complexes—where it activates talin/integrins while weakening the talin-actomyosin linkage, thereby reducing integrin-ligand bond strength, promoting central adhesion sliding, and regulating cell migration speed [PMID:27548916, PMID:37460977]; its ankyrin domain engages KIF21A to link these adhesions to the cortical microtubule stabilization complex, and loss of KANK2 increases sensitivity to microtubule poisons [PMID:29183992, PMID:32195252]. In the cytoplasm, KANK2 sequesters steroid receptor coactivators SRC-2 and SRC-3, a function regulated by casein kinase II-mediated phosphorylation downstream of estrogen signaling and disrupted by a missense mutation (p.Ala670Val) that causes palmoplantar keratoderma and woolly hair [PMID:17476305, PMID:24671081]. KANK2 also interacts with apoptosis-inducing factor (AIF) in mitochondria to suppress caspase-independent apoptosis; apoptotic stimuli trigger KANK2 degradation and AIF nuclear translocation [PMID:22371500]."},"prefetch_data":{"uniprot":{"accession":"Q63ZY3","full_name":"KN motif and ankyrin repeat domain-containing protein 2","aliases":["Ankyrin repeat domain-containing protein 25","Matrix-remodeling-associated protein 3","SRC-1-interacting protein","SIP","SRC-interacting protein","SRC1-interacting protein"],"length_aa":851,"mass_kda":91.2,"function":"Involved in transcription regulation by sequestering in the cytoplasm nuclear receptor coactivators such as NCOA1, NCOA2 and NCOA3 (PubMed:17476305). Involved in regulation of caspase-independent apoptosis by sequestering the proapoptotic factor AIFM1 in mitochondria (PubMed:22371500). Pro-apoptotic stimuli can induce its proteasomal degradation allowing the translocation of AIFM1 to the nucleus to induce apoptosis (PubMed:22371500). Involved in the negative control of vitamin D receptor signaling pathway (PubMed:24671081). Involved in actin stress fibers formation through its interaction with ARHGDIA and the regulation of the Rho signaling pathway (PubMed:17996375, PubMed:25961457). May thereby play a role in cell adhesion and migration, regulating for instance podocytes migration during development of the kidney (PubMed:25961457). Through the Rho signaling pathway may also regulate cell proliferation (By similarity)","subcellular_location":"Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q63ZY3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KANK2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KANK2","total_profiled":1310},"omim":[{"mim_id":"617783","title":"NEPHROTIC SYNDROME, TYPE 16; NPHS16","url":"https://www.omim.org/entry/617783"},{"mim_id":"616099","title":"PALMOPLANTAR KERATODERMA AND WOOLLY HAIR; PPKWH","url":"https://www.omim.org/entry/616099"},{"mim_id":"614612","title":"KN MOTIF- AND ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 4; KANK4","url":"https://www.omim.org/entry/614612"},{"mim_id":"614611","title":"KN MOTIF- AND ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 3; KANK3","url":"https://www.omim.org/entry/614611"},{"mim_id":"614610","title":"KN MOTIF- AND ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 2; KANK2","url":"https://www.omim.org/entry/614610"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KANK2"},"hgnc":{"alias_symbol":["KIAA1518","SIP"],"prev_symbol":["MXRA3","ANKRD25"]},"alphafold":{"accession":"Q63ZY3","domains":[{"cath_id":"1.25.40.20","chopping":"591-694","consensus_level":"medium","plddt":94.1645,"start":591,"end":694},{"cath_id":"1.25.40.20","chopping":"699-835","consensus_level":"medium","plddt":94.2904,"start":699,"end":835}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q63ZY3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q63ZY3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q63ZY3-F1-predicted_aligned_error_v6.png","plddt_mean":60.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KANK2","jax_strain_url":"https://www.jax.org/strain/search?query=KANK2"},"sequence":{"accession":"Q63ZY3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q63ZY3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q63ZY3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q63ZY3"}},"corpus_meta":[{"pmid":"11389839","id":"PMC_11389839","title":"Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses.","date":"2001","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11389839","citation_count":521,"is_preprint":false},{"pmid":"9194702","id":"PMC_9194702","title":"The invasion-associated type III system of Salmonella typhimurium directs the translocation of Sip proteins into the host cell.","date":"1997","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9194702","citation_count":256,"is_preprint":false},{"pmid":"23788333","id":"PMC_23788333","title":"Hydrocarbon-degrading bacteria enriched by the Deepwater Horizon oil spill identified by cultivation and DNA-SIP.","date":"2013","source":"The ISME journal","url":"https://pubmed.ncbi.nlm.nih.gov/23788333","citation_count":174,"is_preprint":false},{"pmid":"27548916","id":"PMC_27548916","title":"Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation.","date":"2016","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27548916","citation_count":133,"is_preprint":false},{"pmid":"12042313","id":"PMC_12042313","title":"CacyBP/SIP, a calcyclin and Siah-1-interacting protein, binds EF-hand proteins of the S100 family.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12042313","citation_count":126,"is_preprint":false},{"pmid":"10992461","id":"PMC_10992461","title":"Identification of group B streptococcal Sip protein, which elicits cross-protective immunity.","date":"2000","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10992461","citation_count":117,"is_preprint":false},{"pmid":"1681027","id":"PMC_1681027","title":"Different scrapie-associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the Sip gene.","date":"1991","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/1681027","citation_count":114,"is_preprint":false},{"pmid":"9325333","id":"PMC_9325333","title":"Bacillus subtilis contains four closely related type I signal peptidases with overlapping substrate specificities. Constitutive and temporally controlled expression of different sip genes.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9325333","citation_count":98,"is_preprint":false},{"pmid":"12823821","id":"PMC_12823821","title":"Sip, an integrase protein with excision, circularization and integration activities, defines a new family of mobile Staphylococcus aureus pathogenicity islands.","date":"2003","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12823821","citation_count":96,"is_preprint":false},{"pmid":"19729475","id":"PMC_19729475","title":"Involvement of sphingosine 1-phosphate (SIP)/S1P3 signaling in cholestasis-induced liver fibrosis.","date":"2009","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19729475","citation_count":92,"is_preprint":false},{"pmid":"18563188","id":"PMC_18563188","title":"Protein-based stable isotope probing (Protein-SIP) reveals active species within anoxic mixed cultures.","date":"2008","source":"The ISME journal","url":"https://pubmed.ncbi.nlm.nih.gov/18563188","citation_count":90,"is_preprint":false},{"pmid":"27242725","id":"PMC_27242725","title":"Unearthing the Ecology of Soil Microorganisms Using a High Resolution DNA-SIP Approach to Explore Cellulose and Xylose Metabolism in Soil.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27242725","citation_count":90,"is_preprint":false},{"pmid":"32127418","id":"PMC_32127418","title":"Analysis of Hi-C data using SIP effectively identifies loops in organisms from C. elegans to mammals.","date":"2020","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/32127418","citation_count":84,"is_preprint":false},{"pmid":"18093158","id":"PMC_18093158","title":"Diversity of the active methanotrophic community in acidic peatlands as assessed by mRNA and SIP-PLFA analyses.","date":"2007","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18093158","citation_count":76,"is_preprint":false},{"pmid":"12067065","id":"PMC_12067065","title":"P53-dependent expression of the stress-induced protein (SIP).","date":"2002","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12067065","citation_count":76,"is_preprint":false},{"pmid":"16818947","id":"PMC_16818947","title":"Radioimmunotherapy of head and neck cancer xenografts using 131I-labeled antibody L19-SIP for selective targeting of tumor vasculature.","date":"2006","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16818947","citation_count":76,"is_preprint":false},{"pmid":"9171284","id":"PMC_9171284","title":"Selectively-infective phage (SIP): a mechanistic dissection of a novel in vivo selection for protein-ligand interactions.","date":"1997","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9171284","citation_count":73,"is_preprint":false},{"pmid":"21342247","id":"PMC_21342247","title":"Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection.","date":"2011","source":"Journal of pineal research","url":"https://pubmed.ncbi.nlm.nih.gov/21342247","citation_count":73,"is_preprint":false},{"pmid":"17244804","id":"PMC_17244804","title":"Real-time PCR targeting the sip gene for detection of group B Streptococcus colonization in pregnant women at delivery.","date":"2007","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17244804","citation_count":69,"is_preprint":false},{"pmid":"9278288","id":"PMC_9278288","title":"Mammalian cell expression of dimeric small immune proteins (SIP).","date":"1997","source":"Protein engineering","url":"https://pubmed.ncbi.nlm.nih.gov/9278288","citation_count":68,"is_preprint":false},{"pmid":"36517261","id":"PMC_36517261","title":"Italian guidelines for the management of irritable bowel syndrome: Joint Consensus from the Italian Societies of: Gastroenterology and Endoscopy (SIGE), 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central adhesion formation and sliding, and decreasing cell migration speed.\",\n      \"method\": \"Co-IP, pulldown assays, FRAP, traction force microscopy, live-cell imaging, siRNA knockdown with phenotypic readouts in migration and adhesion\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding assays, force microscopy, live imaging, KO/KD) with strong mechanistic resolution in a single study\",\n      \"pmids\": [\"27548916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A missense mutation (p.Ala670Val) in KANK2, which encodes the SRC-interacting protein (SIP), abolishes its ability to sequester steroid receptor coactivators (SRC-2 and SRC-3) in the cytoplasm; in patient keratinocytes, SRC-2 and SRC-3 relocalize to the nucleus of epidermal basal cells and vitamin D-induced transactivation is increased, causing palmoplantar keratoderma and woolly hair.\",\n      \"method\": \"Whole-exome sequencing, immunofluorescence localization of SRC coactivators, functional transactivation assay in patient-derived keratinocytes\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient mutation functionally validated by coactivator localization and transactivation assay, linking KANK2 to cytoplasmic sequestration of SRCs\",\n      \"pmids\": [\"24671081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KANK2/SIP (SRC-Interacting Protein), an ankyrin-repeat containing protein, sequesters steroid receptor coactivators (SRCs) in the cytoplasm; estrogen-induced phosphorylation of SIP's PEST domain by casein kinase II causes dissociation of SRCs from SIP and their nuclear translocation, enabling gene coactivation.\",\n      \"method\": \"Co-IP, gain- and loss-of-function experiments, subcellular fractionation, kinase assays, immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple functional readouts, phosphorylation mechanism defined by kinase assay and mutagenesis\",\n      \"pmids\": [\"17476305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KANK2/SIP interacts directly with apoptosis-inducing factor (AIF) in mitochondria and inhibits caspase-independent, AIF-dependent apoptosis; apoptotic stimuli lead to rapid degradation of SIP, liberating AIF to translocate to the nucleus.\",\n      \"method\": \"Co-IP, subcellular fractionation, overexpression and knockdown with apoptosis assays, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction demonstrated by Co-IP, functional consequence confirmed by gain/loss-of-function with specific apoptotic readouts\",\n      \"pmids\": [\"22371500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KANK2 is a key component of integrin αVβ5 integrin adhesion complexes that links these adhesions to microtubules via the cortical microtubule stabilization complex (CMSC); KANK2 knockdown increases sensitivity to microtubule poisons (paclitaxel and vincristine) and decreases cell migration, mimicking integrin αV knockdown.\",\n      \"method\": \"Mass spectrometry-based proteomics of isolated integrin adhesion complexes, siRNA knockdown, cell migration assays, drug sensitivity assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based identification of KANK2 in αVβ5 IACs, validated by knockdown with specific phenotypic readouts\",\n      \"pmids\": [\"32195252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Both KANK1 and KANK2 ankyrin domains bind a ~22 amino acid stretch of KIF21A; crystal structures of KIF21A peptide with KANK1 ankyrin domain and with KANK2 ankyrin domain show KIF21A is recognized by two distinct pockets and adopts helical conformations upon binding.\",\n      \"method\": \"Crystal structure determination, site-directed mutagenesis, biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with mutagenesis validation for both KANK1 and KANK2 complexes\",\n      \"pmids\": [\"29183992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSP70 physically interacts with KANK2; this interaction inhibits apoptosis-inducing factor (AIF) release and apoptosis in septic lung injury; knockdown of KANK2 aggravates apoptosis and tissue damage, while HSP70 treatment reverses these effects.\",\n      \"method\": \"Co-IP, siRNA knockdown, mouse CLP model, LPS-treated human alveolar epithelial cells, apoptosis assays\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo/in vitro KO with functional readout, but from a single lab\",\n      \"pmids\": [\"35327602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KANK2 functionally interacts specifically with talin2 (not talin1) within integrin αVβ5 focal adhesions; talin2 knockdown mimics KANK2 knockdown by increasing microtubule growth velocity, increasing sensitivity to paclitaxel, and reducing cell migration.\",\n      \"method\": \"siRNA knockdown of talin1, talin2, KANK1, KANK2; isolation of integrin adhesion complexes; live-cell confocal imaging of microtubule dynamics; migration assays\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-like genetic approach with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"37460977\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KANK2 is an ankyrin-repeat scaffold protein that localizes to the lateral border of focal adhesions (FA belt) and central adhesions, where it directly binds the talin rod domain (via its KN motif) and KIF21A (via its ankyrin domain) to link integrin αVβ5 adhesion complexes to microtubules through the cortical microtubule stabilization complex; by activating talin/integrins while simultaneously weakening the talin-actomyosin linkage, KANK2 reduces integrin-ligand bond strength and regulates cell migration speed; additionally, KANK2 sequesters steroid receptor coactivators (SRCs) in the cytoplasm (a function disrupted by casein kinase II phosphorylation downstream of estrogen signaling, or by disease-causing mutations causing keratoderma/woolly hair), and interacts with AIF in mitochondria to suppress caspase-independent apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KANK2 is an ankyrin-repeat scaffold protein that coordinates integrin adhesion dynamics, microtubule capture, and transcriptional coactivator localization. At focal adhesions, KANK2 binds the talin rod domain via its KN motif—specifically partnering with talin2 at integrin αVβ5 adhesion complexes—where it activates talin/integrins while weakening the talin-actomyosin linkage, thereby reducing integrin-ligand bond strength, promoting central adhesion sliding, and regulating cell migration speed [PMID:27548916, PMID:37460977]; its ankyrin domain engages KIF21A to link these adhesions to the cortical microtubule stabilization complex, and loss of KANK2 increases sensitivity to microtubule poisons [PMID:29183992, PMID:32195252]. In the cytoplasm, KANK2 sequesters steroid receptor coactivators SRC-2 and SRC-3, a function regulated by casein kinase II-mediated phosphorylation downstream of estrogen signaling and disrupted by a missense mutation (p.Ala670Val) that causes palmoplantar keratoderma and woolly hair [PMID:17476305, PMID:24671081]. KANK2 also interacts with apoptosis-inducing factor (AIF) in mitochondria to suppress caspase-independent apoptosis; apoptotic stimuli trigger KANK2 degradation and AIF nuclear translocation [PMID:22371500].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing KANK2 as a cytoplasmic anchor for steroid receptor coactivators resolved how SRCs are retained outside the nucleus and revealed that estrogen signaling releases them via casein kinase II phosphorylation of KANK2's PEST domain.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, kinase assays, and gain/loss-of-function experiments in cultured cells\",\n      \"pmids\": [\"17476305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether KANK2-SRC sequestration operates in all steroid hormone pathways or is estrogen-specific\",\n        \"Structural basis of SRC recognition by KANK2\",\n        \"In vivo physiological significance of this sequestration mechanism\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that KANK2 directly binds AIF in mitochondria and suppresses caspase-independent apoptosis revealed a second, compartmentally distinct function for the scaffold and showed that apoptotic stimuli liberate AIF by degrading KANK2.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, overexpression and knockdown with apoptosis readouts\",\n      \"pmids\": [\"22371500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The protease or pathway responsible for KANK2 degradation upon apoptotic stimuli\",\n        \"Whether KANK2's adhesion and mitochondrial pools are independently regulated\",\n        \"Structural details of the KANK2–AIF interaction\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of a causative KANK2 missense mutation in palmoplantar keratoderma/woolly hair families connected the SRC-sequestration mechanism to human disease and showed the mutation specifically disrupts cytoplasmic retention of SRC-2/SRC-3 in epidermal basal cells.\",\n      \"evidence\": \"Whole-exome sequencing, immunofluorescence of SRC coactivators, and transactivation assays in patient-derived keratinocytes\",\n      \"pmids\": [\"24671081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which downstream transcriptional programs are deregulated in affected keratinocytes\",\n        \"Whether other KANK2 functions (adhesion, apoptosis) contribute to the skin phenotype\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining KANK2 as a talin-binding protein that localizes to the FA belt and central adhesions established its role as a mechanical regulator: it activates talin/integrins while uncoupling the talin-actomyosin linkage, reducing force transmission and controlling migration speed.\",\n      \"evidence\": \"Co-IP, pulldown, FRAP, traction force microscopy, live-cell imaging, and siRNA knockdown in migrating cells\",\n      \"pmids\": [\"27548916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How KANK2 simultaneously activates talin yet weakens its F-actin linkage at the structural level\",\n        \"Whether KANK2's adhesion role and SRC-sequestration role are coupled or fully independent\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structures of the KANK2 ankyrin domain bound to a KIF21A peptide revealed the atomic basis for microtubule-motor recruitment to adhesion sites, showing KIF21A is recognized by two distinct pockets and adopts helical conformations upon binding.\",\n      \"evidence\": \"X-ray crystallography with site-directed mutagenesis and biochemical binding assays\",\n      \"pmids\": [\"29183992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How KANK2 coordinates simultaneous binding of KIF21A and other ankyrin-domain partners\",\n        \"Whether KANK1 and KANK2 compete for KIF21A at adhesion sites in vivo\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proteomic identification of KANK2 as a component of integrin αVβ5 adhesion complexes linked to the cortical microtubule stabilization complex clarified why KANK2 loss increases sensitivity to microtubule poisons and reduces migration.\",\n      \"evidence\": \"Mass spectrometry of isolated integrin adhesion complexes, siRNA knockdown, drug sensitivity and migration assays\",\n      \"pmids\": [\"32195252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether KANK2 functions at other integrin heterodimer complexes beyond αVβ5\",\n        \"The full composition of the KANK2-containing CMSC at αVβ5 adhesions\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that HSP70 physically interacts with KANK2 and stabilizes its anti-apoptotic function in septic lung injury extended the AIF-sequestration model by identifying an upstream regulator that protects KANK2 from degradation.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, mouse CLP sepsis model, LPS-treated human alveolar epithelial cells\",\n      \"pmids\": [\"35327602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication needed\",\n        \"Whether HSP70 stabilizes KANK2 protein levels or modulates the KANK2–AIF interaction directly\",\n        \"Relevance to non-pulmonary tissues\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that KANK2 functionally partners with talin2 (not talin1) at αVβ5 adhesions refined the molecular specificity of KANK2's adhesion-microtubule coupling and explained isoform-specific phenotypes in microtubule dynamics and drug sensitivity.\",\n      \"evidence\": \"Selective siRNA knockdown of talin1/2 and KANK1/2, integrin adhesion complex isolation, live-cell confocal imaging of microtubule dynamics, migration assays\",\n      \"pmids\": [\"37460977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; structural basis for talin2 selectivity over talin1 not resolved\",\n        \"Whether talin2 preference holds in all cell types and integrin contexts\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KANK2's three major functions—focal adhesion mechanotransduction, SRC coactivator sequestration, and mitochondrial AIF regulation—are coordinated within a single cell, and whether distinct KANK2 pools are independently regulated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study has simultaneously measured adhesion, transcriptional, and apoptotic outputs of KANK2\",\n        \"Post-translational regulation beyond CKII phosphorylation is poorly characterized\",\n        \"In vivo knockout phenotypes in mammalian models have not been systematically described\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\n      \"Cortical microtubule stabilization complex (CMSC)\",\n      \"Integrin αVβ5 adhesion complex\"\n    ],\n    \"partners\": [\n      \"TLN2\",\n      \"KIF21A\",\n      \"AIFM1\",\n      \"NCOA2\",\n      \"NCOA3\",\n      \"HSPA1A\",\n      \"TLN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}