IPPK

Summary

IPPK (inositol-pentakisphosphate 2-kinase, HGNC:14645) is a protein-coding gene on chromosome 9q22.31, encoding Inositol-pentakisphosphate 2-kinase (Q9H8X2). Phosphorylates Ins(1,3,4,5,6)P5 at position 2 to form Ins(1,2,3,4,5,6)P6 (InsP6 or phytate). It is a selective cancer dependency (DepMap: 37.3% of cell lines).

The protein encoded by this gene is a kinase that phosphorylates position 2 of inositol-1,3,4,5,6-pentakisphosphate to form inositol-1,2,3,4,5,6-hexakisphosphate (InsP6). InsP6 has a variety of functions, including stimulation of DNA repair, endocytosis, and mRNA export.

Source: NCBI Gene 64768 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 73 total
• Cancer dependency (DepMap): dependent in 37.3% of screened cell lines
• MANE Select transcript: NM_022755

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14645
Approved symbol	IPPK
Name	inositol-pentakisphosphate 2-kinase
Location	9q22.31
Locus type	gene with protein product
Status	Approved
Aliases	INSP5K2, FLJ13163, IP5K, IPK1
Ensembl gene	ENSG00000127080
Ensembl biotype	protein_coding
OMIM	619043
Entrez	64768

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000287996, ENST00000375522, ENST00000486841, ENST00000870821, ENST00000921769, ENST00000921770

RefSeq mRNA: 1 — MANE Select: NM_022755 NM_022755

CCDS: CCDS6699

Canonical transcript exons

ENST00000287996 — 13 exons

Exon	Start	End
ENSE00000574290	92638001	92638280
ENSE00000711507	92640710	92640782
ENSE00000869920	92658634	92658681
ENSE00000869922	92652573	92652639
ENSE00000869923	92649453	92649574
ENSE00000869924	92648059	92648148
ENSE00000869925	92642752	92642810
ENSE00000869926	92635158	92635308
ENSE00000869927	92634386	92634488
ENSE00000869928	92619486	92619565
ENSE00001031674	92656456	92656551
ENSE00001031676	92613183	92616057
ENSE00001186394	92669908	92670131

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 94.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9544 / max 104.1237, expressed in 1792 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101446	5.9483	1721
101447	3.7381	1606
205559	0.9306	502
101448	0.3374	131

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	94.17	gold quality
skin of leg	UBERON:0001511	92.63	gold quality
esophagus mucosa	UBERON:0002469	92.50	gold quality
skin of abdomen	UBERON:0001416	92.39	gold quality
zone of skin	UBERON:0000014	90.43	gold quality
upper arm skin	UBERON:0004263	88.20	gold quality
tendon of biceps brachii	UBERON:0008188	87.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.10	gold quality
gingival epithelium	UBERON:0001949	87.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.71	gold quality
cerebellar hemisphere	UBERON:0002245	86.44	gold quality
cerebellar cortex	UBERON:0002129	86.33	gold quality
tongue squamous epithelium	UBERON:0006919	86.20	gold quality
upper leg skin	UBERON:0004262	85.97	gold quality
vagina	UBERON:0000996	85.93	gold quality
esophagus squamous epithelium	UBERON:0006920	85.88	gold quality
epithelium of esophagus	UBERON:0001976	85.62	gold quality
squamous epithelium	UBERON:0006914	85.55	gold quality
gingiva	UBERON:0001828	85.44	gold quality
esophagus	UBERON:0001043	85.10	gold quality
cerebellum	UBERON:0002037	84.97	gold quality
cervix epithelium	UBERON:0004801	83.45	silver quality
adenohypophysis	UBERON:0002196	83.18	gold quality
pharyngeal mucosa	UBERON:0000355	82.85	gold quality
right frontal lobe	UBERON:0002810	82.85	gold quality
right atrium auricular region	UBERON:0006631	82.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.64	gold quality
cerebellar vermis	UBERON:0004720	82.46	silver quality
pituitary gland	UBERON:0000007	82.29	gold quality
islet of Langerhans	UBERON:0000006	81.98	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	106.97
E-ANND-3	no	2.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting IPPK, 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-188-3P	100.00	68.76	1240
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3662	99.99	73.82	5684
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-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-10527-5P	99.91	72.28	3754

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 37.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• identified a genomic DNA sequence on chromosome 9 that encodes inositol 1,3,4,5,6-pentakisphosphate 2-kinase; characterization of the enzyme (PMID:12084730)
• IPK1 substrate selection is linked to the ability of each potential substrate to stabilize IPK1. (PMID:24165122)
• IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. (PMID:26976604)
• These results imply that DBP5, GLE1 and IP6 have a conserved and individual function in the cytoplasmic mRNA expression. Variations in phenotype are due to the difference in each function of DBP5, GLE1 and IPPK in intracellular mRNA metabolism. (PMID:29746542)
• Higher urine IPP2K/Cr is associated with less severe kidney lesions at baseline and with preservation of kidney structure over 5 yr in individuals with type 1 diabetes and no clinical evidence of DKD at baseline. (PMID:30132343)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ippk	ENSDARG00000003446
mus_musculus	Ippk	ENSMUSG00000021385
rattus_norvegicus	Ippk	ENSRNOG00000015631
drosophila_melanogaster	Ipk1	FBGN0050295
caenorhabditis_elegans		WBGENE00012466

Protein

Protein identifiers

Inositol-pentakisphosphate 2-kinase — Q9H8X2 (reviewed: Q9H8X2)

Alternative names: IPK1 homolog, Inositol-1,3,4,5,6-pentakisphosphate 2-kinase, Ins(1,3,4,5,6)P5 2-kinase

All UniProt accessions (2): Q9H8X2, X6R9A6

UniProt curated annotations — full annotation on UniProt →

Function. Phosphorylates Ins(1,3,4,5,6)P5 at position 2 to form Ins(1,2,3,4,5,6)P6 (InsP6 or phytate). InsP6 is involved in many processes such as mRNA export, non-homologous end-joining, endocytosis, ion channel regulation. It also protects cells from TNF-induced apoptosis.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitously expressed, with high expression in heart, brain, testis and placenta.

Domain organisation. The EXKPK motif is conserved in inositol-pentakisphosphate 2-kinases of both family 1 and 2.

Similarity. Belongs to the IPK1 type 2 family.

RefSeq proteins (1): NP_073592* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009286	Ins_P5_2-kin	Family
IPR043001	IP5_2-K_N_lobe	Homologous_superfamily

Pfam: PF06090

Enzyme classification (BRENDA):

• EC 2.7.1.158 — inositol-pentakisphosphate 2-kinase (BRENDA: 11 organisms, 30 substrates, 10 inhibitors, 31 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1D-MYO-INOSITOL 1,3,4,5,6-PENTAKISPHOSPHATE	0.0004–0.176	19
ATP	0.0084–0.4	6
1D-MYO-INOSITOL 3,4,5,6-TETRAKISPHOSPHATE	0.0475–0.0792	2
1D-MYO-INOSITOL 1,3,4,6-TETRAKISPHOSPHATE	0.0668	1
1D-MYO-INOSITOL 1,4,5,6-TETRAKISPHOSPHATE	0.056	1
1D-MYO-INOSITOL 1,4,5-TRIPHOSPHATE	0.0006	1
MYO-INOSITOL 1,3,4,5,6-PENTAKISPHOSPHATE	0.119	1

Catalyzed reactions (Rhea), 1 shown:

• 1D-myo-inositol 1,3,4,5,6-pentakisphosphate + ATP = 1D-myo-inositol hexakisphosphate + ADP + H(+) (RHEA:20313)

UniProt features (6 total): sequence variant 2, chain 1, short sequence motif 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H8X2-F1	88.72	0.75

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 (1): 282

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1855167	Synthesis of pyrophosphates in the cytosol
R-HSA-1855191	Synthesis of IPs in the nucleus
R-HSA-1430728	Metabolism
R-HSA-1483249	Inositol phosphate metabolism

MSigDB gene sets: 138 (showing top): GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_RRNA_TRANSCRIPTION, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, LIAO_METASTASIS, chr9q22, GOBP_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_POLYOL_BIOSYNTHETIC_PROCESS, GOBP_ALCOHOL_METABOLIC_PROCESS, GOCC_NUCLEOLUS, SCGGAAGY_ELK1_02

GO Biological Process (3): inositol phosphate biosynthetic process (GO:0032958), inositol phosphate metabolic process (GO:0043647), positive regulation of transcription of nucleolar large rRNA by RNA polymerase I (GO:1901838)

GO Molecular Function (7): ATP binding (GO:0005524), inositol-1,3,4,5,6-pentakisphosphate 2-kinase activity (GO:0035299), molecular adaptor activity (GO:0060090), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Inositol phosphate metabolism	2
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
nuclear lumen	2
inositol phosphate metabolic process	1
polyol biosynthetic process	1
organophosphate biosynthetic process	1
organophosphate metabolic process	1
polyol metabolic process	1
nucleolar large rRNA transcription by RNA polymerase I	1
positive regulation of transcription by RNA polymerase I	1
regulation of transcription of nucleolar large rRNA by RNA polymerase I	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
inositol pentakisphosphate kinase activity	1
molecular_function	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IPPK	IPMK	Q8NFU5	842
IPPK	PPIP5K1	Q6PFW1	804
IPPK	ITPK1	Q13572	748
IPPK	MINPP1	Q9UNW1	689
IPPK	GLE1	Q53GS7	667
IPPK	IP6K1	Q92551	625
IPPK	IP6K2	Q9UHH9	611
IPPK	IP6K3	Q96PC2	574
IPPK	CDIPT	O14735	556
IPPK	INPP1	P49441	528
IPPK	GOLGA6C	A6NDK9	526
IPPK	ADAT1	Q9BUB4	506
IPPK	A0A2R8Y809	A0A2R8Y809	505
IPPK	TBCE	Q15813	505
IPPK	PTPDC1	A2A3K4	470

IntAct

8 interactions, top by confidence:

A	B	Type	Score
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
CPLX4	HSPA8	psi-mi:“MI:0914”(association)	0.350
CD6	CIBAR1	psi-mi:“MI:0914”(association)	0.350
CLEC4A	RBFOX3	psi-mi:“MI:0914”(association)	0.350
CPLX4	SPTB	psi-mi:“MI:0914”(association)	0.350
	EBAG9	psi-mi:“MI:0914”(association)	0.350

BioGRID (186): LPAR1 (Affinity Capture-MS), TYRO3 (Affinity Capture-MS), ENPP4 (Affinity Capture-MS), SELT (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), SC5D (Affinity Capture-MS), CERS4 (Affinity Capture-MS), CERS5 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), TMEM87B (Affinity Capture-MS), GPR50 (Affinity Capture-MS), IPPK (Affinity Capture-MS), ZDHHC17 (Affinity Capture-MS), ATP9A (Affinity Capture-MS), ARL6IP1 (Affinity Capture-MS)

ESM2 similar proteins: A4IIA7, B8AVX5, F4HS99, F4HZK4, F4IVI0, F4JKH6, O75153, O94952, Q0IY07, Q28I29, Q2QKL5, Q2TE74, Q2TSC7, Q3B7T1, Q3TTL0, Q3U034, Q3U3W5, Q4JL91, Q4R3W5, Q5PXE9, Q5R5S1, Q5R9R1, Q5SNL7, Q5SW19, Q5T8I9, Q5W9E7, Q5XVJ4, Q66J91, Q6DFL5, Q6E7H0, Q6GQV7, Q6P1C1, Q6P2P2, Q7XD96, Q7XQZ6, Q7ZXA8, Q8N3J2, Q8NE18, Q8VDH1, Q8W4P9

Diamond homologs: Q4JL91, Q5PXE9, Q6P1C1, Q9H8X2, Q9W2Q7, B8AVX5, Q7XQZ6, Q93YN9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2971 predictions. Top by Δscore:

Variant	Effect	Δscore
9:92616053:CAGAG:C	acceptor_gain	1.0000
9:92616054:AGAG:A	acceptor_gain	1.0000
9:92616055:GAG:G	acceptor_gain	1.0000
9:92616057:GC:G	acceptor_loss	1.0000
9:92616058:C:CC	acceptor_gain	1.0000
9:92616058:C:CG	acceptor_loss	1.0000
9:92619480:CCTCA:C	donor_loss	1.0000
9:92619481:CTCA:C	donor_loss	1.0000
9:92619483:CA:C	donor_loss	1.0000
9:92619484:A:AG	donor_loss	1.0000
9:92619485:C:T	donor_loss	1.0000
9:92634380:GCCCA:G	donor_loss	1.0000
9:92634381:CCCA:C	donor_loss	1.0000
9:92634382:CCA:C	donor_loss	1.0000
9:92634383:CA:C	donor_loss	1.0000
9:92634384:A:C	donor_loss	1.0000
9:92634385:CCT:C	donor_loss	1.0000
9:92634484:TTTTT:T	acceptor_gain	1.0000
9:92634485:TTTT:T	acceptor_gain	1.0000
9:92634486:TTT:T	acceptor_gain	1.0000
9:92634487:TT:T	acceptor_gain	1.0000
9:92634489:C:CC	acceptor_gain	1.0000
9:92634489:CTGAA:C	acceptor_loss	1.0000
9:92634490:T:C	acceptor_loss	1.0000
9:92635152:CCTCA:C	donor_loss	1.0000
9:92635153:CTCA:C	donor_loss	1.0000
9:92635154:TCA:T	donor_loss	1.0000
9:92635156:A:T	donor_loss	1.0000
9:92635157:C:CG	donor_loss	1.0000
9:92635157:CCT:C	donor_gain	1.0000

AlphaMissense

3237 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:92619531:T:G	D402A	0.999
9:92642777:A:G	Y180H	0.999
9:92648059:C:A	K168N	0.999
9:92648059:C:G	K168N	0.999
9:92648087:C:T	C159Y	0.999
9:92648088:A:G	C159R	0.999
9:92648143:T:A	K140N	0.999
9:92648143:T:G	K140N	0.999
9:92648144:T:A	K140I	0.999
9:92649453:C:A	K138N	0.999
9:92649453:C:G	K138N	0.999
9:92615992:T:A	D439V	0.998
9:92619526:A:G	S404P	0.998
9:92619530:G:C	D402E	0.998
9:92619530:G:T	D402E	0.998
9:92619531:T:A	D402V	0.998
9:92619532:C:G	D402H	0.998
9:92619537:G:T	A400D	0.998
9:92640717:A:T	I210K	0.998
9:92640759:G:T	A196D	0.998
9:92642761:A:G	L185P	0.998
9:92642772:A:C	C181W	0.998
9:92642774:A:G	C181R	0.998
9:92648086:A:C	C159W	0.998
9:92648138:C:T	G142E	0.998
9:92669958:A:G	W11R	0.998
9:92669958:A:T	W11R	0.998
9:92615979:C:A	K443N	0.997
9:92615979:C:G	K443N	0.997
9:92619525:G:A	S404F	0.997

dbSNP variants (sampled 300 via entrez): RS1000092409 (9:92666208 C>T), RS1000109915 (9:92654078 T>C), RS1000224266 (9:92660407 C>T), RS1000243571 (9:92623589 G>A,T), RS1000298789 (9:92636724 A>G), RS1000337776 (9:92654724 G>T), RS1000464407 (9:92648943 C>A,G,T), RS1000493971 (9:92649226 C>T), RS1000580811 (9:92641850 G>T), RS1000629648 (9:92636453 A>G), RS1000777426 (9:92635803 A>G), RS1000813683 (9:92654942 C>T), RS1000829805 (9:92666400 A>G), RS1000846327 (9:92625432 T>C), RS1000880738 (9:92666703 G>C)

Disease associations

OMIM: gene MIM:619043 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000817_60	Height	8.000000e-17
GCST002647_29	Height	2.000000e-22
GCST006088_29	Familial squamous cell lung carcinoma	8.000000e-08
GCST008163_446	Height	4.000000e-06
GCST008839_217	Height	6.000000e-11
GCST010725_16	Malaria	9.000000e-06
GCST010725_28	Malaria	6.000000e-06
GCST010725_95	Malaria	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006953	family history of lung cancer

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	affects expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
Amiodarone	increases expression	1
Atrazine	decreases expression	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Methapyrilene	increases methylation	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2ZE	Abcam HEK293T IPPK KO	Transformed cell line	Female
CVCL_D7SE	Ubigene A-549 IPPK KO	Cancer cell line	Male
CVCL_D9HC	Ubigene HEK293 IPPK KO	Transformed cell line	Female

Clinical trials (associated diseases)

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