KANK1

Summary

KANK1 (KN motif and ankyrin repeat domains 1, HGNC:19309) is a protein-coding gene on chromosome 9p24.3, encoding KN motif and ankyrin repeat domain-containing protein 1 (Q14678). Adapter protein that links structural and signaling protein complexes positioned to guide microtubule and actin cytoskeleton dynamics during cell morphogenesis.

The protein encoded by this gene belongs to the Kank family of proteins, which contain multiple ankyrin repeat domains. This family member functions in cytoskeleton formation by regulating actin polymerization. This gene is a candidate tumor suppressor for renal cell carcinoma. Mutations in this gene cause cerebral palsy spastic quadriplegic type 2, a central nervous system development disorder. A t(5;9) translocation results in fusion of the platelet-derived growth factor receptor beta gene (PDGFRB) on chromosome 5 with this gene in a myeloproliferative neoplasm featuring severe thrombocythemia. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 20.

Source: NCBI Gene 23189 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spastic quadriplegic cerebral palsy (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 1,191 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 9
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19309
Approved symbol	KANK1
Name	KN motif and ankyrin repeat domains 1
Location	9p24.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0172, KANK
Ensembl gene	ENSG00000107104
Ensembl biotype	protein_coding
OMIM	607704
Entrez	23189

Gene structure

Transcript identifiers

Ensembl transcripts: 100 — 72 protein_coding, 15 protein_coding_CDS_not_defined, 10 retained_intron, 3 nonsense_mediated_decay

ENST00000354485, ENST00000382286, ENST00000382289, ENST00000382293, ENST00000382297, ENST00000382303, ENST00000441028, ENST00000444793, ENST00000467541, ENST00000475690, ENST00000489369, ENST00000619269, ENST00000654035, ENST00000662822, ENST00000667410, ENST00000674102, ENST00000685049, ENST00000685380, ENST00000685481, ENST00000685590, ENST00000685882, ENST00000685947, ENST00000686420, ENST00000686846, ENST00000687662, ENST00000687796, ENST00000687982, ENST00000688039, ENST00000688321, ENST00000688567, ENST00000688973, ENST00000689126, ENST00000689214, ENST00000689779, ENST00000689926, ENST00000690297, ENST00000690348, ENST00000690372, ENST00000691319, ENST00000691645, ENST00000692130, ENST00000692174, ENST00000692345, ENST00000692757, ENST00000693021, ENST00000693088, ENST00000693143, ENST00000693552, ENST00000693656, ENST00000693668, ENST00000903884, ENST00000903885, ENST00000903886, ENST00000903887, ENST00000903888, ENST00000903889, ENST00000903890, ENST00000903891, ENST00000903892, ENST00000903893, ENST00000903894, ENST00000903895, ENST00000903896, ENST00000903897, ENST00000903898, ENST00000903899, ENST00000903900, ENST00000903901, ENST00000903902, ENST00000903903, ENST00000903904, ENST00000903905, ENST00000903906, ENST00000903907, ENST00000903908, ENST00000903909, ENST00000903910, ENST00000903911, ENST00000917443, ENST00000917444, ENST00000917445, ENST00000949413, ENST00000949414, ENST00000949415, ENST00000949416, ENST00000949417, ENST00000949418, ENST00000949419, ENST00000949420, ENST00000949421, ENST00000949422, ENST00000949423, ENST00000949424, ENST00000949425, ENST00000949426, ENST00000949427, ENST00000949428, ENST00000949429, ENST00000949430, ENST00000949431

RefSeq mRNA: 18 — MANE Select: NM_015158 NM_001256876, NM_001256877, NM_001354331, NM_001354332, NM_001354333, NM_001354334, NM_001354335, NM_001354336, NM_001354337, NM_001354338, NM_001354339, NM_001354340, NM_001354341, NM_001354342, NM_001354343, NM_001354344, NM_015158, NM_153186

CCDS: CCDS34976, CCDS6441, CCDS94372, CCDS94373, CCDS94374

Canonical transcript exons

ENST00000382297 — 12 exons

Exon	Start	End
ENSE00001633361	734748	734835
ENSE00001664566	732378	732617
ENSE00003484124	710804	713464
ENSE00003494848	745173	746103
ENSE00003498289	731158	731266
ENSE00003558231	742205	742405
ENSE00003588489	744491	744589
ENSE00003589673	740792	740934
ENSE00003607149	676890	677009
ENSE00003615984	738285	738504
ENSE00003640962	730051	730248
ENSE00003719697	504695	504754

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.0504 / max 334.3087, expressed in 1707 samples.

FANTOM5 promoters (31 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95793	4.7187	933
95799	2.6577	1092
95800	2.4641	853
95759	2.2755	780
95782	2.1771	695
95789	1.8153	499
95754	0.8270	536
95783	0.5837	218
95788	0.5098	124
95762	0.4895	141

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
blood vessel layer	UBERON:0004797	99.35	gold quality
cartilage tissue	UBERON:0002418	98.84	gold quality
descending thoracic aorta	UBERON:0002345	98.23	gold quality
ascending aorta	UBERON:0001496	97.93	gold quality
thoracic aorta	UBERON:0001515	97.93	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.77	gold quality
aorta	UBERON:0000947	97.27	gold quality
popliteal artery	UBERON:0002250	96.78	gold quality
tibial artery	UBERON:0007610	96.77	gold quality
gingival epithelium	UBERON:0001949	96.68	gold quality
left ventricle myocardium	UBERON:0006566	96.67	gold quality
cardiac atrium	UBERON:0002081	96.54	gold quality
saphenous vein	UBERON:0007318	96.51	gold quality
right atrium auricular region	UBERON:0006631	96.42	gold quality
right coronary artery	UBERON:0001625	96.31	gold quality
myocardium	UBERON:0002349	96.27	gold quality
choroid plexus epithelium	UBERON:0003911	96.27	gold quality
skin of hip	UBERON:0001554	96.09	gold quality
gingiva	UBERON:0001828	95.98	gold quality
urethra	UBERON:0000057	95.95	gold quality
apex of heart	UBERON:0002098	95.95	gold quality
heart	UBERON:0000948	95.92	gold quality
heart left ventricle	UBERON:0002084	95.85	gold quality
right lobe of liver	UBERON:0001114	95.84	gold quality
cardiac ventricle	UBERON:0002082	95.84	gold quality
tibia	UBERON:0000979	95.56	gold quality
coronary artery	UBERON:0001621	95.35	gold quality
left coronary artery	UBERON:0001626	95.34	gold quality
lower esophagus mucosa	UBERON:0035834	95.33	gold quality
upper leg skin	UBERON:0004262	95.32	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	2417.79
E-GEOD-131882	yes	2378.96
E-HCAD-35	yes	24.96
E-GEOD-93593	yes	4.85
E-GEOD-76312	no	100.00
E-ENAD-27	no	3.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

68 targeting KANK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-5580-3P	99.70	69.41	2052

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 31)

• Kank is localized to 9p24 and plays a role in cell growth (PMID:12133830)
• Human Kank gene has several alternative first exons. (PMID:15823577)
• Kank can bind to beta-catenin and regulate the subcellular distribution of beta-catenin. (PMID:16968744)
• Data suggest that Kank negatively regulates the formation of actin stress fibers and cell migration through the inhibition of RhoA activity, which is controlled by binding of Kank to 14-3-3 in PI3K-Akt signaling. (PMID:18458160)
• These results suggest that KIF21A regulates the distribution of Kank1 and that KIF21A mutations associated with congenital fibrosis of the extraocular muscles type 1 enhanced the accumulation of Kank1 in the membrane fraction. (PMID:19559006)
• KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia. (PMID:20164854)
• BIG1 and KANK1 play roles in regulating cell polarity during directed migration in wound healing. (PMID:22084092)
• ANKRD15 encodes the kidney ankyrin repeat-containing protein. (PMID:22876580)
• Our case suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. (PMID:23454270)
• Thus, the human brain glioma apoptosis induced by upregulation of the Kank1 gene is closely relevant to the mitochondrial pathway. (PMID:24399197)
• Follow-up replication analyses in up to an additional 21,345 participants identified three new fasting plasma glucose loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. (PMID:25187374)
• identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. (PMID:25961457)
• primary results revealed new function of Kank1 for nasopharyngeal cancer (PMID:25973051)
• liprin beta-1 is associated with expression of kank 1 and 2 proteins in melanoma (PMID:26739330)
• Here, the authors show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5beta and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. (PMID:27410476)
• KANK1 inhibits Malignant peripheral nerve sheath tumors cell growth though CXXC5 mediated apoptosis. (PMID:28067315)
• Kank1 plays a crucial role in regulating the activity of RhoA through retrieving excess Daam1 and balancing the activities of RhoA and its effectors. (PMID:28284839)
• Upregulating the Kank1 gene can inhibit the progress of gastric cancer. (PMID:28731169)
• Several key residues (i.e. Thr-1147, Leu-1152, Leu-1153, and Tyr-1154) at the C-terminal half of the KIF21A KBD peptide contact with the hydrophobic patch formed by Tyr-1176, Met-1209, Leu-1210, Leu-1213, and Leu-1248 from KANK1. (PMID:29158259)
• KANK1 aberrations do not frequently cause cerebral palsy but represent a risk factor for autism spectrum disorders. (PMID:29729439)
• Low KANK1 expression is associated with lung cancer progression. (PMID:29956815)
• Small interstitial 9p24.3 deletions principally involving KANK1 are likely benign copy number variants. (PMID:30684669)
• KANK1 protein is required for targeting microtubules to focal adhesions. (PMID:31114072)
• Aberrant Kank1 expression regulates YAP to promote apoptosis and inhibit proliferation in OSCC. (PMID:31338836)
• These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions. (PMID:31389241)
• KANK1 regulates paclitaxel resistance in lung adenocarcinoma A549 cells. (PMID:32064933)
• Long non-coding RNA CASC2 enhances cisplatin sensitivity in oral squamous cell cancer cells by the miR-31-5p/KANK1 axis. (PMID:32787433)
• KANK1-NTRK3 fusions define a subset of BRAF mutation negative renal metanephric adenomas. (PMID:33046021)
• KANK family proteins in cancer. (PMID:33309958)
• TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation. (PMID:34349117)
• Identification and Characterization of the Roles of circCASP9 in Gastric Cancer Based on a circRNA-miRNA-mRNA Regulatory Network. (PMID:35320976)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	kank1a	ENSDARG00000060102
danio_rerio	kank1b	ENSDARG00000060584
danio_rerio	kank3	ENSDARG00000076566
mus_musculus	Kank1	ENSMUSG00000032702
rattus_norvegicus	Kank1	ENSRNOG00000016023
drosophila_melanogaster	Kank	FBGN0027596
caenorhabditis_elegans		WBGENE00006882

Paralogs (3): KANK4 (ENSG00000132854), KANK3 (ENSG00000186994), KANK2 (ENSG00000197256)

Protein

Protein identifiers

KN motif and ankyrin repeat domain-containing protein 1 — Q14678 (reviewed: Q14678)

Alternative names: Ankyrin repeat domain-containing protein 15, Kidney ankyrin repeat-containing protein

All UniProt accessions (17): Q14678, A0A8I5KNW9, A0A8I5KP85, A0A8I5KRP2, A0A8I5KSV2, A0A8I5KT40, A0A8I5KTS9, A0A8I5KUD8, A0A8I5KUI5, A0A8I5KUM3, A0A8I5KVK4, A0A8I5KXH8, A0A8I5KZ49, A0A8I5QKT2, A0A8J9BYE6, Q5W0W2, Q5W0W3

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that links structural and signaling protein complexes positioned to guide microtubule and actin cytoskeleton dynamics during cell morphogenesis. At focal adhesions (FAs) rims, organizes cortical microtubule stabilizing complexes (CMSCs) and directly interacts with major FA component TLN1, forming macromolecular assemblies positioned to control microtubule-actin crosstalk at the cell edge. Recruits KIF21A in CMSCs at axonal growth cones and regulates axon guidance by suppressing microtubule growth without inducing microtubule disassembly once it reaches the cell cortex. Interacts with ARFGEF1 and participates in establishing microtubule-organizing center (MTOC) orientation and directed cell movement in wound healing. Regulates actin stress fiber formation and cell migration by inhibiting RHOA activation in response to growth factors; this function involves phosphorylation through PI3K/Akt signaling and may depend on the competitive interaction with 14-3-3 adapter proteins to sequester them from active complexes. Inhibits the formation of lamellipodia but not of filopodia; this function may depend on the competitive interaction with BAIAP2 to block its association with activated RAC1. Inhibits fibronectin-mediated cell spreading; this function is partially mediated by BAIAP2. In the nucleus, is involved in beta-catenin-dependent activation of transcription. During cell division, may regulate DAAM1-dependent RHOA activation that signals centrosome maturation and chromosomal segregation. May also be involved in contractile ring formation during cytokinesis. Potential tumor suppressor for renal cell carcinoma.

Subunit / interactions. Part of a cortical microtubule stabilization complex (CMSC) composed of KANK1, PPFIA1, PPFIBP1, ERC1/ELKS, PHLDB2/LL5beta, CLASPs, KIF21A and possibly additional interactors; within CMSCs KANK1 and PHLDB2/LL5beta seem to be the core components for recruiting microtubule-binding proteins KIF21A and CLASPs, whereas PPFIA1, PPFIBP1 and ERC1/ELKS serve as scaffolds for protein clustering. Interacts (via KN motif) with TLN1 (via R7 domain); this mediates CMSC clustering around focal adhesions. Interacts (via CC1 domain, residues 244-339) with PPFIBP1. Interacts (via ANK repeats 1-5) with KIF21A (via residues 1146-1167). Interacts with YWHAQ; the interaction requires KANK1 phosphorylation at Ser-325 and is enhanced by growth factor stimulation. Interacts with YWHAB, YWHAG, YWHAE, YWHAH, YWHAZ and SFN; the interaction requires KANK1 phosphorylation at Ser-325. Interacts with ARFGEF1; however, colocalization cannot be experimentally confirmed. Interacts with BAIAP2. Interacts with CTNNB1. Interacts (via coiled coil domain) with DAAM1 (via coiled coil domain).

Subcellular location. Cytoplasm. Cell cortex. Cell projection. Ruffle membrane. Nucleus Cytoplasm. Nucleus.

Tissue specificity. Widely expressed. Isoform 1 is predominantly expressed in heart and kidney. Isoform 2 probably is widely expressed at basic levels.

Disease relevance. Cerebral palsy, spastic quadriplegic 2 (CPSQ2) [MIM:612900] A non-progressive disorder of movement and/or posture resulting from defects in the developing central nervous system. Affected individuals manifest congenital hypotonia evolving over the first year to spastic quadriplegia with accompanying transient nystagmus and varying degrees of intellectual disability. Neuroimaging shows brain atrophy and ventriculomegaly. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14678-1	1, Kank-L	yes
Q14678-2	2, Kank-S

RefSeq proteins (18): NP_001243805, NP_001243806, NP_001341260, NP_001341261, NP_001341262, NP_001341263, NP_001341264, NP_001341265, NP_001341266, NP_001341267, NP_001341268, NP_001341269, NP_001341270, NP_001341271, NP_001341272, NP_001341273, NP_055973, NP_694856 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR021939	KN_motif	Conserved_site
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR047184	KANK1-4	Family

Pfam: PF12075, PF12796

UniProt features (85 total): mutagenesis site 21, helix 17, sequence variant 10, region of interest 8, compositionally biased region 7, repeat 6, short sequence motif 6, coiled-coil region 3, modified residue 2, strand 2, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5YBU	X-RAY DIFFRACTION	1.89
8IW0	X-RAY DIFFRACTION	2.1
5YBJ	X-RAY DIFFRACTION	2.34
8IVZ	X-RAY DIFFRACTION	2.8
8AS9	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14678-F1	54.50	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 186, 325

Mutagenesis-validated functional residues (21):

Position	Phenotype
41	abolishes binding to tln1 and impairs cmsc assembly at the focal adhesion rims leading to increased microtubule growth r
42	abolishes binding to tln1 and impairs cmsc assembly at the focal adhesion rims leading to increased microtubule growth r
43	nuclear localization; when associated a-52; a-125; a-129; a-134; a-613; a-616; a-620 and a-622. abolishes binding to tln
44	abolishes binding to tln1 and impairs cmsc assembly at the focal adhesion rims leading to increased microtubule growth r
52	nuclear localization; when associated a-43; a-125; a-129; a-134; a-613; a-616; a-620 and a-622.
65–68	enhanced cytoplasmic localization; when associated with 979-a–a-981 and 991-a-a-992.
125	nuclear localization; when associated a-43; a-52; a-129; a-134; a-613; a-616; a-620 and a-622.
129	nuclear localization; when associated a-43; a-52; a-125; a-134; a-613; a-616; a-620 and a-622.
134	nuclear localization; when associated a-43; a-52; a-125; a-129; a-613; a-616; a-620 and a-622.
325	abolishes phosphorylation by pkb. abolishes interaction with ywhab; ywhag; ywhae; ywhah; ywhaq; ywhaz and sfn.
613	nuclear localization; when associated a-43; a-52; a-125; a-129; a-134; a-616; a-620 and a-622.
616	nuclear localization; when associated a-43; a-52; a-125; a-129; a-134; a-613; a-620 and a-622.
620	nuclear localization; when associated a-43; a-52; a-125; a-129; a-134; a-613; a-616 and a-622.
622	nuclear localization; when associated a-43; a-52; a-125; a-129; a-134; a-613; a-616 and a-620.
979–981	enhanced cytoplasmic localization; when associated with 65-a–a-68 and 991-a-a-992.
991–992	enhanced cytoplasmic localization; when associated with 65-a–68 and 979-a–a-981.
1197	4.5-fold decrease in binding to kif21a.
1197	very weak binding affinity for kif21a.
1276	abolishes binding to kif21a.
1298	15-fold decrease in binding to kif21a.
1300	10-fold decrease in binding to kif21a.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9673768	Signaling by membrane-tethered fusions of PDGFRA or PDGFRB
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-8939211	ESR-mediated signaling
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-9671555	Signaling by PDGFR in disease

MSigDB gene sets: 334 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOZGIT_ESR1_TARGETS_DN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION

GO Biological Process (17): cell population proliferation (GO:0008283), negative regulation of neuron projection development (GO:0010977), actin cytoskeleton organization (GO:0030036), positive regulation of Wnt signaling pathway (GO:0030177), negative regulation of cell migration (GO:0030336), negative regulation of actin filament polymerization (GO:0030837), regulation of Rho protein signal transduction (GO:0035023), negative regulation of Rho protein signal transduction (GO:0035024), cortical microtubule organization (GO:0043622), negative regulation of insulin receptor signaling pathway (GO:0046627), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of wound healing (GO:0090303), podocyte cell migration (GO:0090521), negative regulation of substrate adhesion-dependent cell spreading (GO:1900025), negative regulation of ruffle assembly (GO:1900028), regulation of establishment of cell polarity (GO:2000114), negative regulation of lamellipodium morphogenesis (GO:2000393)

GO Molecular Function (3): beta-catenin binding (GO:0008013), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell cortex (GO:0005938), ruffle membrane (GO:0032587), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
ESR-mediated signaling	1
Signaling by PDGFR in disease	1
Disease	1
Signaling by Nuclear Receptors	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
Rho protein signal transduction	2
protein binding	2
cell periphery	2
cellular process	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
cytoskeleton organization	1
actin filament-based process	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
actin filament polymerization	1
regulation of actin filament polymerization	1
negative regulation of protein polymerization	1
negative regulation of cytoskeleton organization	1
negative regulation of supramolecular fiber organization	1
regulation of small GTPase mediated signal transduction	1
regulation of Rho protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
cortical cytoskeleton organization	1
cytoplasmic microtubule organization	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
epithelial cell migration	1
negative regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1

Protein interactions and networks

STRING

1814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KANK1	TLN1	Q9Y490	980
KANK1	TLN2	Q9Y4G6	977
KANK1	DOCK8	Q8NF50	934
KANK1	DMRT1	Q9Y5R6	916
KANK1	PHLDB2	Q86SQ0	894
KANK1	KIF21A	Q7Z4S6	835
KANK1	ERC1	Q8IUD2	810
KANK1	AP4M1	O00189	797
KANK1	SEPSECS	Q9HD40	768
KANK1	PPFIBP1	Q86W92	679
KANK1	PPFIA1	Q13136	669
KANK1	GAD1	Q99259	653
KANK1	PXN	P49023	643
KANK1	ARHGDIA	P52565	636
KANK1	VCL	P18206	599

IntAct

57 interactions, top by confidence:

A	B	Type	Score
KANK1	KIF21A	psi-mi:“MI:0914”(association)	0.750
KIF21A	KANK1	psi-mi:“MI:0914”(association)	0.750
KIF21A	KANK1	psi-mi:“MI:0915”(physical association)	0.750
KANK1	KIF21A	psi-mi:“MI:0915”(physical association)	0.750
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
BAIAP2	RAC1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
CA10	WDHD1	psi-mi:“MI:0914”(association)	0.640
BAIAP2	KANK1	psi-mi:“MI:0915”(physical association)	0.640
KANK1	BAIAP2	psi-mi:“MI:0915”(physical association)	0.640
ARFGEF1	KANK1	psi-mi:“MI:0914”(association)	0.630
ARFGEF1	KANK1	psi-mi:“MI:0407”(direct interaction)	0.630
ARFGEF1	KANK1	psi-mi:“MI:0915”(physical association)	0.630
YWHAE	RGS12	psi-mi:“MI:0914”(association)	0.610
YWHAQ	KANK1	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (60): KANK1 (Affinity Capture-RNA), KANK1 (Affinity Capture-RNA), KANK1 (Affinity Capture-RNA), KANK1 (Affinity Capture-RNA), KANK1 (Affinity Capture-MS), KANK1 (Affinity Capture-MS), KANK1 (Affinity Capture-MS), KANK1 (Affinity Capture-MS), KANK1 (Affinity Capture-MS), KANK1 (Affinity Capture-RNA), KANK1 (Affinity Capture-MS), KANK1 (Proximity Label-MS), YWHAG (Affinity Capture-Western), YWHAE (Affinity Capture-Western), YWHAH (Affinity Capture-Western)

ESM2 similar proteins: A0M8S4, A0M8T5, B9EJA2, E9Q238, O70240, O88566, P57095, Q00PJ1, Q07DV1, Q07DW4, Q07DX4, Q07DY4, Q07E15, Q07E28, Q07E41, Q09YG9, Q09YI1, Q09YJ3, Q09YK4, Q09YM8, Q0VA20, Q108T9, Q13625, Q14678, Q2IBA2, Q2IBB2, Q2IBD4, Q2IBE6, Q2IBF7, Q2IBF8, Q2QL82, Q2QLA2, Q2QLB3, Q2QLF8, Q2QLG9, Q3UIL6, Q5NBX1, Q5RDH2, Q5XG16, Q6A098

Diamond homologs: D3ZD05, E9Q238, Q14678, Q1LZH7, Q5T7N3, Q63ZY3, Q6NY19, Q6P9J5, Q8BX02, Q9Z1P7, X1WE18, P93002, A4II29, F1MJR8, O83515, P0C0T2, Q01317, Q05823, Q05921, Q21920, Q24009, Q5M9H0, Q5SUE8, Q5U4T7, Q5U5A6, Q5XJ13, Q68DC2, Q6AI12, Q6GQX6, Q6ZW76, Q7T3X9, Q7T3Y0, Q7Z6K4, Q8IWB6, Q91ZA8, Q99MQ1, Q9CZK6, Q9H694, Q9IA00, O08764

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KANK1	“down-regulates activity”	BAIAP2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
VEGFA-VEGFR2 Pathway	5	17.9×	9e-04
Membrane Trafficking	9	8.6×	2e-04
Vesicle-mediated transport	9	8.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1191 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	669
Likely benign	300
Benign	97

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
146577	GRCh38/hg38 9p24.3(chr9:556625-703693)x1	Pathogenic
2908	NC_000009.12:g.(606181_654801)_831563del	Pathogenic
402188	NM_015158.5(KANK1):c.3237C>G (p.Ile1079Met)	Likely pathogenic

SpliceAI

5704 predictions. Top by Δscore:

Variant	Effect	Δscore
9:506320:T:G	donor_gain	1.0000
9:710799:TCTA:T	acceptor_loss	1.0000
9:710801:TA:T	acceptor_loss	1.0000
9:710802:A:AG	acceptor_gain	1.0000
9:710802:AG:A	acceptor_gain	1.0000
9:710803:G:GG	acceptor_gain	1.0000
9:710803:GG:G	acceptor_gain	1.0000
9:710803:GGA:G	acceptor_gain	1.0000
9:710803:GGAA:G	acceptor_gain	1.0000
9:731156:A:AG	acceptor_gain	1.0000
9:731157:G:GG	acceptor_gain	1.0000
9:731157:GC:G	acceptor_gain	1.0000
9:731157:GCAT:G	acceptor_gain	1.0000
9:731265:GG:G	donor_gain	1.0000
9:731266:GG:G	donor_gain	1.0000
9:732613:GAGAG:G	donor_gain	1.0000
9:734743:TTCA:T	acceptor_loss	1.0000
9:734744:TCAG:T	acceptor_loss	1.0000
9:734745:CA:C	acceptor_loss	1.0000
9:734746:A:AG	acceptor_gain	1.0000
9:734746:AG:A	acceptor_gain	1.0000
9:734747:G:GT	acceptor_gain	1.0000
9:734747:GG:G	acceptor_gain	1.0000
9:734747:GGT:G	acceptor_gain	1.0000
9:734747:GGTA:G	acceptor_gain	1.0000
9:734747:GGTAT:G	acceptor_gain	1.0000
9:738281:GCA:G	acceptor_loss	1.0000
9:738282:CA:C	acceptor_loss	1.0000
9:738283:A:AG	acceptor_gain	1.0000
9:738283:AG:A	acceptor_loss	1.0000

AlphaMissense

8917 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:711587:T:C	L274P	1.000
9:738440:C:A	N1163K	1.000
9:738440:C:G	N1163K	1.000
9:740817:C:A	N1193K	1.000
9:740817:C:G	N1193K	1.000
9:740827:T:C	Y1197H	1.000
9:740843:T:C	L1202S	1.000
9:740852:T:C	L1205P	1.000
9:742213:G:C	Q1235H	1.000
9:742213:G:T	Q1235H	1.000
9:742227:T:A	L1240Q	1.000
9:742227:T:C	L1240P	1.000
9:742233:T:A	V1242D	1.000
9:742235:A:C	S1243R	1.000
9:742237:T:A	S1243R	1.000
9:742237:T:G	S1243R	1.000
9:742298:G:C	D1264H	1.000
9:742299:A:T	D1264V	1.000
9:742317:C:A	A1270D	1.000
9:742325:T:C	C1273R	1.000
9:742329:C:A	A1274D	1.000
9:742331:A:C	S1275R	1.000
9:742333:C:A	S1275R	1.000
9:742333:C:G	S1275R	1.000
9:711596:T:C	L277P	0.999
9:738315:T:A	W1122R	0.999
9:738315:T:C	W1122R	0.999
9:738453:T:C	Y1168H	0.999
9:738453:T:G	Y1168D	0.999
9:738456:A:C	S1169R	0.999

dbSNP variants (sampled 300 via entrez): RS1000018872 (9:719701 G>C), RS1000029402 (9:566446 A>G), RS1000036789 (9:479630 T>G), RS1000042946 (9:663548 T>C), RS1000044609 (9:728901 C>G), RS1000049250 (9:557059 T>C), RS1000069391 (9:663731 G>C), RS1000069709 (9:719875 C>A,G,T), RS1000076230 (9:508408 A>G), RS1000078319 (9:715711 A>G), RS1000089898 (9:470970 G>GCCCT), RS1000095209 (9:729109 C>T), RS1000095941 (9:699609 A>C,T), RS1000097008 (9:508217 C>G), RS1000103251 (9:562123 G>A,C,T)

Disease associations

OMIM: gene MIM:607704 | disease phenotypes: MIM:612900, MIM:181500, MIM:243700

GenCC curated gene-disease

Disease	Classification	Inheritance
spastic quadriplegic cerebral palsy	Supportive	Autosomal recessive
cerebral palsy, spastic quadriplegic, 2	Limited	Autosomal dominant
nephrotic syndrome	Limited	Autosomal recessive

Mondo (7): cerebral palsy, spastic quadriplegic, 2 (MONDO:0013033), schizophrenia (MONDO:0005090), combined immunodeficiency due to DOCK8 deficiency (MONDO:0009478), amyotrophic lateral sclerosis (MONDO:0004976), neurodevelopmental disorder (MONDO:0700092), spastic quadriplegic cerebral palsy (MONDO:0016215), nephrotic syndrome (MONDO:0005377)

Orphanet (5): Inherited congenital spastic tetraplegia (Orphanet:210141), Combined immunodeficiency due to DOCK8 deficiency (Orphanet:217390), Amyotrophic lateral sclerosis (Orphanet:803), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

9 total (11 of 9 shown, HPO-id order):

HPO	Term
HP:0000639	Nystagmus
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0002059	Cerebral atrophy
HP:0002119	Ventriculomegaly
HP:0002510	Spastic tetraplegia
HP:0003577	Congenital onset
HP:0012275	Autosomal dominant inheritance with maternal imprinting
HP:0100021	Cerebral palsy
HP:0100753	Schizophrenia
HP:0007354	Amyotrophic lateral sclerosis

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002586_2	Fasting plasma glucose	1.000000e-09
GCST003264_145	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003542_8	Night sleep phenotypes	3.000000e-08
GCST005784_7	Bone mineral density (femoral neck) in inflammatory bowel disease	5.000000e-06
GCST006105_2	Eye morphology	2.000000e-06
GCST006462_31	Uterine fibroids	3.000000e-12
GCST006628_45	Systolic blood pressure	6.000000e-10
GCST007018_23	Serum bilirubin levels in metabolic syndrome	8.000000e-06
GCST008112_1	Proinsulin levels (early-phase conversion)	2.000000e-09
GCST009066_17	Mosaic loss of chromosome Y (Y chromosome dosage)	4.000000e-08
GCST009067_17	Mosaic loss of chromosome Y (Y chromosome dosage)	2.000000e-06
GCST009158_4	Uterine fibroids	2.000000e-13
GCST011587_13	Fasting blood glucose	2.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0007785	femoral neck bone mineral density
EFO:0006335	systolic blood pressure
EFO:0004570	bilirubin measurement
EFO:0004467	insulin measurement
EFO:0007783	mosaic loss of chromosome Y measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
D065886	Neurodevelopmental Disorders	F03.625
C567867	Cerebral Palsy, Spastic Quadriplegic, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
Valproic Acid	affects expression, decreases expression, decreases methylation, affects cotreatment, increases expression	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression	2
potassium chromate(VI)	decreases expression, increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Formaldehyde	decreases expression	2
Nickel	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
ochratoxin A	increases expression	1
benzo(e)pyrene	decreases methylation, increases methylation	1
rutecarpine	decreases expression	1
aflatoxin B2	affects methylation, decreases methylation	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
chromium hexavalent ion	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, increases expression	1
bisphenol S	increases expression	1

Clinical trials (associated diseases)

406 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder