KHDRBS1

Summary

KHDRBS1 (KH RNA binding domain containing, signal transduction associated 1, HGNC:18116) is a protein-coding gene on chromosome 1p35.2, encoding KH domain-containing, RNA-binding, signal transduction-associated protein 1 (Q07666). Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors.

This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3’-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10657 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ovarian failure (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 59 total — 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006559

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18116
Approved symbol	KHDRBS1
Name	KH RNA binding domain containing, signal transduction associated 1
Location	1p35.2
Locus type	gene with protein product
Status	Approved
Aliases	Sam68, p62, FLJ34027
Ensembl gene	ENSG00000121774
Ensembl biotype	protein_coding
OMIM	602489
Entrez	10657

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000307714, ENST00000327300, ENST00000484270, ENST00000492989, ENST00000906249, ENST00000906250, ENST00000906251, ENST00000916417, ENST00000916418, ENST00000916419, ENST00000967223, ENST00000967224

RefSeq mRNA: 2 — MANE Select: NM_006559 NM_001271878, NM_006559

CCDS: CCDS350, CCDS60067

Canonical transcript exons

ENST00000327300 — 9 exons

Exon	Start	End
ENSE00001824447	32013868	32014377
ENSE00001938497	32042527	32043877
ENSE00003477894	32031524	32031640
ENSE00003496162	32038552	32038619
ENSE00003496606	32037835	32038036
ENSE00003588620	32039515	32039573
ENSE00003596778	32030298	32030422
ENSE00003606770	32033188	32033334
ENSE00003636617	32036910	32037043

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 164.9298 / max 975.9728, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1934	163.1588	1828
201453	0.8974	545
1935	0.8736	202

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.55	gold quality
ganglionic eminence	UBERON:0004023	99.28	gold quality
cortical plate	UBERON:0005343	99.18	gold quality
parietal pleura	UBERON:0002400	99.17	gold quality
tendon of biceps brachii	UBERON:0008188	99.17	gold quality
visceral pleura	UBERON:0002401	99.11	gold quality
ventricular zone	UBERON:0003053	99.10	gold quality
superficial temporal artery	UBERON:0001614	99.06	gold quality
pleura	UBERON:0000977	99.05	gold quality
embryo	UBERON:0000922	99.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.00	gold quality
gingival epithelium	UBERON:0001949	98.83	gold quality
lower lobe of lung	UBERON:0008949	98.67	gold quality
tibia	UBERON:0000979	98.65	gold quality
epithelium of nasopharynx	UBERON:0001951	98.58	gold quality
thymus	UBERON:0002370	98.38	gold quality
endometrium epithelium	UBERON:0004811	98.34	gold quality
gingiva	UBERON:0001828	98.22	gold quality
epithelial cell of pancreas	CL:0000083	98.15	gold quality
upper arm skin	UBERON:0004263	98.12	gold quality
esophagus squamous epithelium	UBERON:0006920	98.01	gold quality
mammary duct	UBERON:0001765	97.95	gold quality
hair follicle	UBERON:0002073	97.95	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.93	gold quality
squamous epithelium	UBERON:0006914	97.93	gold quality
epithelium of mammary gland	UBERON:0003244	97.91	gold quality
mucosa of urinary bladder	UBERON:0001259	97.88	gold quality
renal glomerulus	UBERON:0000074	97.86	gold quality
cerebellar vermis	UBERON:0004720	97.84	gold quality
endometrium	UBERON:0001295	97.81	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.25
E-CURD-122	yes	5.53
E-MTAB-6142	no	151.16
E-CURD-114	no	7.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
AR	Unknown
IGF2	Activation
LEP	Activation

Upstream regulators (CollecTRI, top): AR, E2F3, E2F4, TFE3

miRNA regulators (miRDB)

147 targeting KHDRBS1, 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-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-4795-3P	100.00	74.62	4024
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6499-3P	99.90	66.38	1212

Literature-anchored findings (GeneRIF, showing 40)

• studies demonstrate that a lower level of constitutive Sam68 expression, followed by further down-regulation by HIV-1 infection, contributes to impaired Rev function in astrocytes and that Sam68 may play an important role in Rev nuclear export (PMID:11932418)
• Down-modulation of Sam68 expression caused exclusive nuclear retention and colocalization of both Rev and CRM1. (PMID:12134041)
• Here we describe the identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a protein that specifically interacts with Sam68 in vitro and in vivo. (PMID:12370808)
• the distinct potential of Fyn and Lck to phosphorylate Sam68 is likely controlled by the interaction of the kinase SH3 domain with the linker and Sam68, possibly on a competitive binding basis. (PMID:12370810)
• Sam68 functioned to enhance the cytoplasmic utilization of RNA containing the CTE. These results suggest that Sam68 may interact with specific RNAs in the nucleus to provide a “mark” that affects their cytoplasmic fate (PMID:12482964)
• tr-kit promotes the formation of a multimolecular complex composed of Fyn, PLCgamma1 and Sam68, which allows phosphorylation of PLCgamma1 by Fyn, and may modulate RNA metabolism. (PMID:14647465)
• The participation of Sam68 in signaling suggests that it may function as an adaptor molecule, working as a dock to recruit other signaling molecules. (PMID:15619005)
• Sam68 is involved in Rev-mediated RNA export and is required for HIV production. (PMID:15701759)
• Sam68 suppresses BRK-induced cell proliferation, and regulates intranuclear localization and cell cycle progression (PMID:16179349)
• Tyrosine 440 was identified as a principal modulator of Sam68 (KHDRBS1) localization to the nucleus and this site was phosphorylated in response to EGF treatment. (PMID:16179349)
• Sam68 (KHDRBS1) is a positive regulator of adipocyte differentiation and a negative regulator of osteoblast differentiation in mice. (PMID:16362077)
• shows Sam68 is modified by SUMO, and demonstrate that the SUMO E3 ligase (PIAS1) (protein inhibitor of activated STAT1) can enhance Sam68 sumoylation (PMID:16568089)
• Results suggest that hsp22 specifically binds to Sam68 and modulates its activity, thus playing a role in the post-transcriptional regulation of gene expression. (PMID:16795043)
• identified 23 mRNAs that are associated with the immunoprecipitated endogenous Sam68 protein complex. Five of the identified mRNAs were validated by co-immunoprecipitation assay followed by reverse transcription PCR (PMID:17179751)
• Our results indicate that Sam68 plays a role in the regulation of Bcl-x alternative splicing and that tyrosine phosphorylation of Sam68 by Src-like kinases can switch its role from proapoptotic to antiapoptotic in live cells. (PMID:17371836)
• The results suggest that the RG repeats conserved in Sam68 and SLM proteins may function as an auxiliary RNA binding domain and arginine methylation may eliminate or reduce an RNA binding ability of the proteins (PMID:17764653)
• results strongly suggest that Sam68 contributes to transformation by oncogenic Vav1 (PMID:17855053)
• The signaling adaptor p62 is induced by Ras, its levels are increased in human tumors, and it is required for Ras-induced survival and transformation. (PMID:18394557)
• The authors demonstrate that inhibition of HIV expression by Sam68DeltaC is correlated with a loss of PABP1 binding with no attendant change in polyadenosine tail length of the affected RNAs. (PMID:18957126)
• Sam68 interacts with unspliced HIV-1 RNA and that other members of the STAR/GSG protein family promote viral RNA 3’ end processing (PMID:19091369)
• Sam68 cytoplasmic mutants potently suppress Nef expression. (PMID:19150430)
• Sam68 blocks HIV-1 structural protein synthesis. (PMID:19254361)
• Sam68 interacts with HIV-1 Rev protein and directly participates in nuclear exportation of HIV-1 unspliced or singly spliced RNA. (PMID:19535902)
• Sam68 is recruited into stress granules through complexing with TIA-1 in response to oxidative stress (PMID:19615357)
• SAM68 could represent a novel and useful prognostic marker for renal cell carcinoma. High SAM68 expression and cytoplasmic localization are associated with poor overall survival in renal cell carcinoma patients (PMID:19755649)
• identified hnRNP L as a novel Sam68-interacting protein partner. (PMID:19912651)
• Our results identify Sam68 as the first splicing factor to affect CCND1 alternative splicing in prostate cancer cells (PMID:20028857)
• Sam68 is sequestered by expanded CGG repeats and thereby loses its splicing-regulatory function. (PMID:20186122)
• In vivo splicing assays showed that Sam68 triggers SMN2 exon-7 skipping. (PMID:20186123)
• the Qua1 homodimerization domain is required for regulation of alternative splicing by Sam68. (PMID:20610388)
• Sam68 modulation of SF2/ASF splicing is controlled by epithelial cell-derived soluble factors that act through the ERK1/2 signaling pathway to regulate Sam68 phosphorylation. (PMID:20876280)
• These results strongly suggest the participation of Sam68 in leptin receptor signaling in human trophoblastic cells, and therefore, Sam68 may mediate some of the leptin effects in placenta. (PMID:21035519)
• The results show that DDX3, eIF5A, and hRIP enhanced HIV-1 internal ribosomal entry site-mediated translation, whereas Sam68 does not. (PMID:21360055)
• Met receptors induce Sam68-dependent cell migration by activation of alternate extracellular signal-regulated kinase family members (PMID:21489997)
• Sam68 is required for both NF-kappaB activation and apoptosis signaling by the TNF receptor (PMID:21620750)
• High Sam68 expression is associated with pancreatic cancer progression. (PMID:21642356)
• These results demonstrated for the first time that Hsp22 regulates Sam68 expression and the ratio of Sam68 to Hsp22 may determine the proliferative potential of glioblastoma cells. (PMID:21678403)
• Sam68 could induce cervical cancer lymph node metastasis through regulating epithelial-mesenchymal transition (PMID:21700735)
• The tyrosine-rich domain of Sam68 is bound in a bent conformation to the APC groove. (PMID:22000517)
• Sam68 interacts with insulin receptor substrate (IRS)-1 in basal conditions, and insulin increases the affinity between these two partners. (PMID:22005517)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	khdrbs1a	ENSDARG00000052856
danio_rerio	khdrbs1b	ENSDARG00000070475
mus_musculus	Khdrbs1	ENSMUSG00000028790
rattus_norvegicus	Khdrbs1	ENSRNOG00000046794
drosophila_melanogaster	qkr58E-3	FBGN0022984
drosophila_melanogaster	qkr58E-2	FBGN0022985
drosophila_melanogaster	qkr58E-1	FBGN0022986
drosophila_melanogaster	qkr54B	FBGN0022987
drosophila_melanogaster	CG4021	FBGN0034659
drosophila_melanogaster	CG10384	FBGN0034731
drosophila_melanogaster	CG3927	FBGN0034739
drosophila_melanogaster	nsr	FBGN0034740

Paralogs (4): KHDRBS2 (ENSG00000112232), QKI (ENSG00000112531), KHDRBS3 (ENSG00000131773), SF1 (ENSG00000168066)

Protein

Protein identifiers

KH domain-containing, RNA-binding, signal transduction-associated protein 1 — Q07666 (reviewed: Q07666)

Alternative names: GAP-associated tyrosine phosphoprotein p62, Src-associated in mitosis 68 kDa protein, p21 Ras GTPase-activating protein-associated p62, p68

All UniProt accessions (1): Q07666

UniProt curated annotations — full annotation on UniProt →

Function. Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors. Once phosphorylated, functions as an adapter protein in signal transduction cascades by binding to SH2 and SH3 domain-containing proteins. Role in G2-M progression in the cell cycle. Represses CBP-dependent transcriptional activation apparently by competing with other nuclear factors for binding to CBP. Also acts as a putative regulator of mRNA stability and/or translation rates and mediates mRNA nuclear export. Positively regulates the association of constitutive transport element (CTE)-containing mRNA with large polyribosomes and translation initiation. According to some authors, is not involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species according to. RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds to RNA containing 5’-[AU]UAA-3’ as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). Can regulate CD44 alternative splicing in a Ras pathway-dependent manner. In cooperation with HNRNPA1 modulates alternative splicing of BCL2L1 by promoting splicing toward isoform Bcl-X(S), and of SMN1. Can regulate alternative splicing of NRXN1 and NRXN3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners. In a neuronal activity-dependent manner cooperates synergistically with KHDRBS2/SLIM-1 in regulation of NRXN1 exon skipping at AS4. The cooperation with KHDRBS2/SLIM-1 is antagonistic for regulation of NXRN3 alternative splicing at AS4. Isoform 3, which is expressed in growth-arrested cells only, inhibits S phase.

Subunit / interactions. Self-associates to form homooligomers when bound to RNA, oligomerization appears to be limited when binding to proteins; dimerization increases RNA affinity. Forms a trimeric complex in the nucleus consisting of BANP, HDAC6 and KHDRBS1/SAM68; HDAC6 keeps KHDRBS1 in a deacetylated state which inhibits the inclusion of CD44 alternate exons. The complex is disrupted by MAPK1/MAPK3-mediated phosphorylation of BANP which results in BANP export to the cytoplasm. This facilitates acetylation of KHDRBS1 and CD44 variant exon inclusion. Interacts with KHDRBS3/SLIM-2. Interacts with KHDRBS2/SLIM-1; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity. Interacts with RASA1, LCK, FYN, PTPN6, PLCG1, GRB2, CBL, JAK3, PIK3R, STAT3, APC, HNRNPA1. Interacts with PTK6 (via SH3 and SH2 domains). Forms a complex with ILF2, ILF3, YLPM1, RBMX, NCOA5 and PPP1CA. Does not interact with TPR. Interacts with PRMT1. Binds WBP4/FBP21 (via WW domains), FNBP4/FBP30 (via WW domains). Interacts (via Arg/Gly-rich-flanked Pro-rich regions) with FYN (via the SH3 domain). Interacts with the non-receptor tyrosine kinase SRMS; the interaction leads to phosphorylation of KHDRBS1. Interacts with ZBTB7A; negatively regulates KHDRBS1 splicing activity toward BCL2L1.

Subcellular location. Nucleus. Cytoplasm. Membrane.

Tissue specificity. Ubiquitously expressed in all tissue examined. Isoform 1 is expressed at lower levels in brain, skeletal muscle, and liver whereas isoform 3 is intensified in skeletal muscle and in liver.

Post-translational modifications. Tyrosine phosphorylated by several non-receptor tyrosine kinases including LCK, FYN and JAK3. Also tyrosine phosphorylated by the non-receptor tyrosine kinase SRMS in an EGF-dependent manner. Negatively correlates with ability to bind RNA but required for many interactions with proteins. Phosphorylation by PTK6 negatively regulates its RNA binding ability. Phosphorylation by PTK6 at Tyr-440 dictates the nuclear localization of KHDRBS1. Phosphorylation at Tyr-387 disrupts interaction with APC. Phosphorylation at tyrosine residues by FYN inverts activity on modulation of BCL2L1 alternative splicing. Acetylated. Positively correlates with ability to bind RNA. Deacetylated by HDAC6; this regulates alternative splicing by inhibiting the inclusion of CD44 alternate exons. Arginine methylation is required for nuclear localization. Also can affect interaction with other proteins. Inhibits interaction with Src-like SH3 domains, but not interaction with WW domains of WBP4/FBP21 and FNBP4/FBP30.

Domain organisation. The KH domain is required for binding to RNA. The Pro-rich domains are flanked by Arg/Gly-rich motifs which can be asymmetric dimethylated on arginine residues to give the DMA/Gly-rich regions. Selective methylation on these motifs can modulate protein-protein interactions.

Similarity. Belongs to the KHDRBS family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q07666-1	1	yes
Q07666-2	2
Q07666-3	3, DeltaKH

RefSeq proteins (2): NP_001258807, NP_006550* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004087	KH_dom	Domain
IPR032335	Sam68-YY	Domain
IPR032571	Qua1_dom	Domain
IPR036612	KH_dom_type_1_sf	Homologous_superfamily
IPR045071	BBP-like	Family
IPR055256	KH_1_KHDC4/BBP-like	Domain

Pfam: PF16274, PF16568, PF22675

UniProt features (64 total): modified residue 31, mutagenesis site 11, region of interest 7, cross-link 5, compositionally biased region 4, splice variant 2, helix 2, chain 1, domain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
7Z8A	X-RAY DIFFRACTION	2.06
7ZAC	X-RAY DIFFRACTION	2.08
3QHE	X-RAY DIFFRACTION	2.4
7ZAB	X-RAY DIFFRACTION	2.46
7Z9A	X-RAY DIFFRACTION	2.57
7ZAF	X-RAY DIFFRACTION	2.71
7Z89	X-RAY DIFFRACTION	2.76
7ZAM	X-RAY DIFFRACTION	2.79
7Z9B	X-RAY DIFFRACTION	3.33
2XA6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07666-F1	65.54	0.27

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 (36): 18, 20, 29, 33, 45, 52, 58, 84, 113, 150, 175, 183, 282, 284, 291, 304, 310, 315, 320, 320 …

Mutagenesis-validated functional residues (11):

Position	Phenotype
103	impairs homodimerization.
110	impairs homodimerization.
118	disrupts homodimerization, impairs influence on alternative splicing.
229	disrupts binding to poly(a). decreased binding to the bcl2l1 mrna. loss of function in bcl2l1 splicing. changed nuclear
241	fails to influence alternative splicing of cd44, nrxn2 and nrxn3.
381	disrupts interaction with apc.
383	impairs interaction with apc.
384	disrupts interaction with apc.
435	no effect on the nuclear localization.
440	completely blocks nuclear localization.
443	no effect on the nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8849468	PTK6 Regulates Proteins Involved in RNA Processing
R-HSA-162582	Signal Transduction
R-HSA-8848021	Signaling by PTK6
R-HSA-9006927	Signaling by Non-Receptor Tyrosine Kinases

MSigDB gene sets: 0 (showing top):

GO Biological Process (16): G1/S transition of mitotic cell cycle (GO:0000082), G2/M transition of mitotic cell cycle (GO:0000086), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA processing (GO:0006397), spermatogenesis (GO:0007283), regulation of apoptotic process (GO:0042981), regulation of RNA splicing (GO:0043484), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of translational initiation (GO:0045948), regulation of RNA export from nucleus (GO:0046831), positive regulation of RNA export from nucleus (GO:0046833), T cell receptor signaling pathway (GO:0050852), regulation of cell cycle (GO:0051726), cell surface receptor signaling pathway (GO:0007166), regulation of mRNA splicing, via spliceosome (GO:0048024)

GO Molecular Function (15): DNA binding (GO:0003677), RNA binding (GO:0003723), mRNA binding (GO:0003729), poly(A) binding (GO:0008143), poly(U) RNA binding (GO:0008266), SH3 domain binding (GO:0017124), protein domain specific binding (GO:0019904), signaling adaptor activity (GO:0035591), SH2 domain binding (GO:0042169), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), molecular function inhibitor activity (GO:0140678), protein tyrosine kinase binding (GO:1990782), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), protein-containing complex (GO:0032991), Grb2-Sos complex (GO:0070618)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by PTK6	1
Signaling by Non-Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
mitotic cell cycle	2
mitotic cell cycle phase transition	2
RNA export from nucleus	2
nucleic acid binding	2
protein domain specific binding	2
protein binding	2
cell cycle G1/S phase transition	1
cell cycle G2/M phase transition	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
RNA processing	1
mRNA metabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
apoptotic process	1
regulation of programmed cell death	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
translational initiation	1
regulation of translational initiation	1
positive regulation of translation	1
regulation of nucleobase-containing compound transport	1
regulation of nucleocytoplasmic transport	1
positive regulation of nucleobase-containing compound transport	1
positive regulation of nucleocytoplasmic transport	1
regulation of RNA export from nucleus	1
antigen receptor-mediated signaling pathway	1
cell cycle	1
regulation of cellular process	1
signal transduction	1
mRNA splicing, via spliceosome	1

Protein interactions and networks

STRING

2630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KHDRBS1	SRC	P12931	949
KHDRBS1	HNRNPK	P61978	867
KHDRBS1	RASA1	P20936	866
KHDRBS1	YTHDC1	Q96MU7	809
KHDRBS1	HNRNPA1	P09651	791
KHDRBS1	RBMX	P38159	782
KHDRBS1	PRMT1	Q99873	775
KHDRBS1	U2AF2	P26368	753
KHDRBS1	HNRNPA2B1	P22626	740
KHDRBS1	PTK6	Q13882	737
KHDRBS1	FYN	P06241	731
KHDRBS1	DROSHA	Q9NRR4	729
KHDRBS1	HNRNPC	P07910	728
KHDRBS1	HNRNPDL	O14979	720
KHDRBS1	PTBP1	P26599	720

IntAct

336 interactions, top by confidence:

A	B	Type	Score
HNRNPA1	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.870
HNRNPA1	KHDRBS1	psi-mi:“MI:0403”(colocalization)	0.870
GRB2	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.870
FYN	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.850
KHDRBS1	FYN	psi-mi:“MI:0915”(physical association)	0.850
LCK	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.830
KHDRBS1	HCK	psi-mi:“MI:0915”(physical association)	0.780
PLCG1	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.690
APC	KHDRBS1	psi-mi:“MI:0407”(direct interaction)	0.670
KHDRBS1	RBMX	psi-mi:“MI:0915”(physical association)	0.670
KHDRBS1	HNRNPK	psi-mi:“MI:0915”(physical association)	0.670
LYN	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.610
SRC	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.570
GAS7	SFPQ	psi-mi:“MI:0914”(association)	0.560
KHDRBS1	EFEMP1	psi-mi:“MI:0915”(physical association)	0.550
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530

BioGRID (602): ZBTB7A (Two-hybrid), ZBTB7A (Reconstituted Complex), ZBTB7A (Affinity Capture-Western), KHDRBS1 (Affinity Capture-Western), KHDRBS1 (Reconstituted Complex), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-Western), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS), KHDRBS1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMV4, A2VDN6, A4IGK4, B2GV05, O75525, O88532, O94776, P52756, P54288, P58405, P59326, Q07666, Q08289, Q08BJ2, Q0VFL3, Q0VFL7, Q12906, Q13033, Q15459, Q1RMU5, Q562A2, Q5REX3, Q5SFM8, Q5U231, Q5VWX1, Q60749, Q64012, Q64213, Q68FH0, Q68FJ8, Q6GPM1, Q6PCR6, Q8BTF8, Q8CC27, Q8K4Z5, Q8UUW7, Q8UVD9, Q8VGC3, Q91V33, Q91YE7

Diamond homologs: G5EFF1, O01367, O74555, O75525, P0CO44, P0CO45, P13230, Q07666, Q08BJ2, Q0VFL3, Q0WLR1, Q12186, Q15637, Q17339, Q32NN2, Q4P0H7, Q4WXV6, Q54BM5, Q5AED9, Q5VWX1, Q5W9D5, Q5W9D6, Q5W9D7, Q60749, Q64213, Q6BSP4, Q6C187, Q6FW77, Q6IRN2, Q6P0D0, Q6P104, Q750X2, Q75GR5, Q7JJZ8, Q8GWR3, Q8GYR4, Q8NIW7, Q8UUW7, Q91V33, Q91XU1

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
PTK6	unknown	KHDRBS1	phosphorylation
BANP	“down-regulates activity”	KHDRBS1	binding
KHDRBS1	“down-regulates activity”	CREBBP	binding
CHUK	“up-regulates activity”	KHDRBS1	phosphorylation
INSR	“up-regulates activity”	KHDRBS1	phosphorylation
SRC	“up-regulates activity”	KHDRBS1	phosphorylation
FYN	“up-regulates activity”	KHDRBS1	phosphorylation
CDK1	unknown	KHDRBS1	phosphorylation
PTK6	up-regulates	KHDRBS1	phosphorylation
MAPK1	up-regulates	KHDRBS1	phosphorylation
KHDRBS1	“up-regulates activity”	NRXN1	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 185 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
Regulation of signaling by CBL	10	37.9×	3e-11
Regulation of KIT signaling	8	36.7×	5e-09
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	9	35.7×	5e-10
Downstream signal transduction	9	26.1×	7e-09
Signaling by ALK	6	26.1×	5e-06
Signaling by PTK6	6	24.9×	6e-06
Signaling by Non-Receptor Tyrosine Kinases	6	24.9×	6e-06
Signaling by CSF1 (M-CSF) in myeloid cells	9	23.8×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytoplasmic translation	5	31.6×	8e-05
negative regulation of inflammatory response to antigenic stimulus	7	26.8×	4e-06
stimulatory C-type lectin receptor signaling pathway	5	23.3×	3e-04
Fc-gamma receptor signaling pathway involved in phagocytosis	5	22.4×	4e-04
positive regulation of Rac protein signal transduction	5	20.6×	4e-04
leukocyte migration	5	19.9×	5e-04
peptidyl-tyrosine phosphorylation	7	18.8×	3e-05
ephrin receptor signaling pathway	7	15.3×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	34
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
929733	NM_006559.3(KHDRBS1):c.1262C>T (p.Pro421Leu)	Likely pathogenic

SpliceAI

1188 predictions. Top by Δscore:

Variant	Effect	Δscore
1:32014373:GGCAG:G	donor_gain	1.0000
1:32014374:GCAG:G	donor_gain	1.0000
1:32014374:GCAGG:G	donor_gain	1.0000
1:32014375:C:T	donor_gain	1.0000
1:32014376:AGG:A	donor_loss	1.0000
1:32014378:GTA:G	donor_loss	1.0000
1:32014379:T:A	donor_loss	1.0000
1:32030295:CAGA:C	acceptor_loss	1.0000
1:32030296:A:AG	acceptor_gain	1.0000
1:32030296:AGAAA:A	acceptor_loss	1.0000
1:32030297:G:GA	acceptor_gain	1.0000
1:32030297:GA:G	acceptor_gain	1.0000
1:32030297:GAA:G	acceptor_gain	1.0000
1:32030297:GAAA:G	acceptor_gain	1.0000
1:32030297:GAAAT:G	acceptor_gain	1.0000
1:32030420:AAG:A	donor_gain	1.0000
1:32030421:AG:A	donor_gain	1.0000
1:32030421:AGGT:A	donor_loss	1.0000
1:32030422:GG:G	donor_gain	1.0000
1:32030423:G:GC	donor_loss	1.0000
1:32030423:G:GG	donor_gain	1.0000
1:32030424:T:A	donor_loss	1.0000
1:32031522:A:AG	acceptor_gain	1.0000
1:32031523:G:GG	acceptor_gain	1.0000
1:32033184:A:AG	acceptor_gain	1.0000
1:32033184:ATAG:A	acceptor_gain	1.0000
1:32033185:T:G	acceptor_gain	1.0000
1:32033186:A:AG	acceptor_gain	1.0000
1:32033186:AG:A	acceptor_gain	1.0000
1:32033186:AGGAG:A	acceptor_gain	1.0000

AlphaMissense

2824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:32014315:T:A	L107H	1.000
1:32014315:T:C	L107P	1.000
1:32014320:G:C	A109P	1.000
1:32014336:T:A	L114H	1.000
1:32014336:T:C	L114P	1.000
1:32014347:T:C	F118L	1.000
1:32014349:C:A	F118L	1.000
1:32014349:C:G	F118L	1.000
1:32014357:C:A	A121D	1.000
1:32014366:T:C	L124P	1.000
1:32014369:T:C	L125P	1.000
1:32030382:T:C	L156P	1.000
1:32030391:G:C	R159P	1.000
1:32030394:T:A	V160E	1.000
1:32030400:T:A	I162K	1.000
1:32030400:T:C	I162T	1.000
1:32030400:T:G	I162R	1.000
1:32030402:C:A	P163T	1.000
1:32030402:C:T	P163S	1.000
1:32030403:C:A	P163H	1.000
1:32030403:C:G	P163R	1.000
1:32030414:T:G	Y167D	1.000
1:32031524:T:C	F170L	1.000
1:32031525:T:C	F170S	1.000
1:32031526:C:A	F170L	1.000
1:32031526:C:G	F170L	1.000
1:32031527:A:G	N171D	1.000
1:32031529:T:A	N171K	1.000
1:32031529:T:G	N171K	1.000
1:32031530:T:A	F172I	1.000

dbSNP variants (sampled 300 via entrez): RS1000043721 (1:32032897 T>G), RS1000108684 (1:32053405 A>G), RS1000149128 (1:32020616 T>A), RS1000185792 (1:32035540 G>C), RS1000188658 (1:32042149 G>C), RS1000191376 (1:32041729 A>T), RS1000456656 (1:32059170 AAAAAAAAAAAAAAAC>A), RS1000523623 (1:32043307 C>G,T), RS1000546325 (1:32014451 C>G,T), RS1000644878 (1:32034602 A>G), RS1000801719 (1:32043654 C>G), RS1000813293 (1:32028256 C>G), RS1000830380 (1:32030932 A>G), RS1000931988 (1:32034294 G>A,T), RS1000938903 (1:32024957 T>C)

Disease associations

OMIM: gene MIM:602489 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ovarian failure	Strong	Autosomal dominant

Mondo (1): primary ovarian failure (MONDO:0005387)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_36	Body mass index	9.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795190 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.93	Kd	117.7	nM	CHEMBL3752910
6.93	ED50	117.7	nM	CHEMBL3752910
5.43	IC50	3750	nM	MOLIBRESIB
5.02	Kd	9619	nM	CHEMBL5653589
5.02	ED50	9619	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148620: Binding affinity to human KHDRBS1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1177	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178551: Inhibition of KHDRBS1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	3.7500	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148620: Binding affinity to human KHDRBS1 incubated for 45 mins by Kinobead based pull down assay	kd	9.6190	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, affects cotreatment, decreases expression, affects splicing	3
bisphenol A	decreases expression, affects cotreatment, affects expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
geraniol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
methylparaben	increases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	increases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	affects expression	1
calfactant	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Irinotecan	decreases expression	1
Resveratrol	increases expression	1
Acetaminophen	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651662	Binding	Binding affinity to human KHDRBS1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists