KSR1

Summary

KSR1 (kinase suppressor of ras 1, HGNC:6465) is a protein-coding gene on chromosome 17q11.2, encoding Kinase suppressor of Ras 1 (Q8IVT5). Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases.

Enables 14-3-3 protein binding activity and ATP binding activity. Involved in positive regulation of MAPK cascade. Located in cytosol; endoplasmic reticulum; and membrane. Part of protein-containing complex. Implicated in breast adenocarcinoma. Biomarker of breast cancer.

Source: NCBI Gene 8844 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 143 total
• Druggable target: yes
• MANE Select transcript: NM_001394583

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6465
Approved symbol	KSR1
Name	kinase suppressor of ras 1
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RSU2
Ensembl gene	ENSG00000141068
Ensembl biotype	protein_coding
OMIM	601132
Entrez	8844

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 7 protein_coding, 6 protein_coding_CDS_not_defined, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000398982, ENST00000398985, ENST00000398988, ENST00000577823, ENST00000578981, ENST00000579309, ENST00000579399, ENST00000579961, ENST00000580430, ENST00000580822, ENST00000581975, ENST00000582311, ENST00000582410, ENST00000583370, ENST00000583525, ENST00000583998, ENST00000644418, ENST00000644974

RefSeq mRNA: 5 — MANE Select: NM_001394583 NM_001367810, NM_001394583, NM_001394584, NM_001394585, NM_014238

CCDS: CCDS58532, CCDS92281

Canonical transcript exons

ENST00000644974 — 21 exons

Exon	Start	End
ENSE00001201644	27610067	27610198
ENSE00001201649	27609196	27609329
ENSE00001201655	27607914	27608010
ENSE00001279501	27605434	27605813
ENSE00002371795	27585657	27585661
ENSE00002726270	27456448	27456874
ENSE00003460343	27604680	27604728
ENSE00003466715	27601360	27601401
ENSE00003524247	27582646	27583105
ENSE00003543047	27597268	27597436
ENSE00003573675	27588475	27588535
ENSE00003601444	27592361	27592422
ENSE00003625609	27590811	27590894
ENSE00003658307	27617295	27617428
ENSE00003665678	27592520	27592626
ENSE00003665734	27611494	27611629
ENSE00003671374	27550568	27550708
ENSE00003689973	27577492	27577639
ENSE00003694506	27603834	27603888
ENSE00003820720	27623314	27626435
ENSE00003822897	27621193	27621273

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 98.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2096 / max 163.6229, expressed in 1642 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159962	9.5671	1595
159970	0.6333	381
159961	0.5693	278
159973	0.3139	96
159975	0.0649	29
159974	0.0310	16
159976	0.0129	8
159964	0.0084	3
159963	0.0052	3
208103	0.0037	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.26	gold quality
sural nerve	UBERON:0015488	96.16	gold quality
oocyte	CL:0000023	95.56	gold quality
right lobe of thyroid gland	UBERON:0001119	95.26	gold quality
endocervix	UBERON:0000458	95.24	gold quality
metanephros cortex	UBERON:0010533	94.54	gold quality
left lobe of thyroid gland	UBERON:0001120	94.46	gold quality
gall bladder	UBERON:0002110	94.07	gold quality
lower esophagus mucosa	UBERON:0035834	94.02	gold quality
thyroid gland	UBERON:0002046	93.87	gold quality
ectocervix	UBERON:0012249	93.60	gold quality
esophagus mucosa	UBERON:0002469	93.26	gold quality
left testis	UBERON:0004533	93.15	gold quality
left ovary	UBERON:0002119	93.14	gold quality
endothelial cell	CL:0000115	93.05	gold quality
body of uterus	UBERON:0009853	93.05	gold quality
right testis	UBERON:0004534	92.86	gold quality
tibial nerve	UBERON:0001323	92.78	gold quality
stromal cell of endometrium	CL:0002255	92.62	gold quality
right ovary	UBERON:0002118	92.59	gold quality
granulocyte	CL:0000094	92.23	gold quality
pharyngeal mucosa	UBERON:0000355	92.02	gold quality
pancreas	UBERON:0001264	91.96	gold quality
secondary oocyte	CL:0000655	91.95	gold quality
monocyte	CL:0000576	91.94	gold quality
mononuclear cell	CL:0000842	91.56	gold quality
upper lobe of left lung	UBERON:0008952	91.51	gold quality
gastrocnemius	UBERON:0001388	91.44	gold quality
leukocyte	CL:0000738	91.32	gold quality
omental fat pad	UBERON:0010414	91.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.12
E-CURD-10	no	64.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CDK4

Upstream regulators (CollecTRI, top): CTCF, PAX1

miRNA regulators (miRDB)

88 targeting KSR1, 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-30E-5P	100.00	76.32	3242
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-149-3P	99.72	68.22	3963

Literature-anchored findings (GeneRIF, showing 34)

• KSR1 kinase activity is essential for anti-apoptotic protection of the intestinal epithelium [review] (PMID:15520853)
• KSR1-mediated regulation of ERK activity represents a novel determinant of CDDP sensitivity of cancer cells. (PMID:15899786)
• 1,25D selectively increases the expression of the gene encoding kinase suppressor of Ras-1 (KSR-1) in HL60 cells (PMID:16732322)
• Human KSR1 proteins promote assembly of multivalent Raf.MEK complexes that are required for c-Raf kinase activation and functional coupling of active kinases to downstream substrates. (PMID:18332145)
• human 14-3-3gamma binds to the ERK1/2 molecular scaffold KSR1, which is mediated by the C-terminal stretch of 14-3-3gamma (PMID:18426801)
• Down-regulation of KSR1 in pancreatic cancer xenografts by antisense oligonucleotide correlates with tumor drug uptake. (PMID:18719367)
• KSR1 regulated the threshold required for MAPK activation in T cells without affecting the nature of the response. (PMID:19188442)
• DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. (PMID:19718030)
• Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells. (PMID:20945381)
• KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels (PMID:21435442)
• Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K. (PMID:21555152)
• simulations constitute a multi-dimensional exploration of how EGF-dependent EGFR endocytosis and ERK activation are dynamically affected by scaffolds KSR and MP1, co-regulated by Cbl-CIN85 and Endophilin A1 (PMID:21829671)
• VRK2A can form a high molecular size complex with both MEK1 and KSR1; the KSR1 complex assembled and retained by VRK2A in the endoplasmic reticulum can have a modulatory effect on the signal mediated by MAPK,locally affecting the magnitude of its responses (PMID:22752157)
• the atypical C1 domain, the CC-SAM domain is required to target KSR-1 to the plasma membrane. (PMID:23250398)
• Elevated levels of phosphorylated KSR were detected in the nuclear fractions. (PMID:23416464)
• Data indicate that phosphorylation of BRAF by AMPK disrupts its association with KSR1. (PMID:24095280)
• Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity. (PMID:24129246)
• KSR1 stabilizes BRCA1 by reducing BRCA1 ubiquitination, inhibits tumor growth through BRCA1, and regulates BRCA1 stability via elevated BARD1 abundance and increased BRCA1-BARD1 interaction (PMID:24909178)
• Data show that caveolin-1 is necessary for optimal KSR1-dependent ERK activation by growth factors and oncogenic Ras. (PMID:25002533)
• KSR1 rs2241906 variants may predict survival in patients with advanced ERalpha+ BC treated with adjuvant TAM. (PMID:25287073)
• KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in papillary thyroid cancer. (PMID:25608512)
• the relative mRNA copy values of KSR1, ERK1 and ERK2 in the cancer tissues were 2.43 +/- 0.49, 2.10 +/- 0.44 and 3.65 +/- 0.94..EGb 761 enhanced the chemotherapy sensitivity through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer (PMID:25962735)
• Data show that neurofibromin 2 (Merlin) suppresses proliferation and adhesion, at least partly, through inhibiting kinase suppressor of Ras 1 (KSR1) and DCAF1 protein. (PMID:26549023)
• Upregulation of KSR1 is associated with Colorectal cancer. (PMID:26673620)
• praja2 regulates KSR1 stability and mitogenic signaling. (PMID:27195677)
• These results suggest that Rap1 activation of ERKs requires PKA phosphorylation and KSR binding. (PMID:28003362)
• findings demonstrate that KSR-MEK complexes allosterically activate BRAF through the action of N-terminal regulatory region and kinase domain contacts and challenge the accepted role of KSR as a scaffold for MEK recruitment to RAF (PMID:29433126)
• Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer (PMID:29596465)
• Erbin interacted with kinase suppressor of Ras 1 (KSR1) and displaced it from the RAF/MEK/ERK complex to prevent signal propagation..These findings establish the scaffold protein Erbin as a negative regulator of EMT and tumorigenesis in colorectal cancer through direct suppression of Akt and RAS/RAF signaling (PMID:29980571)
• Findings demonstrate a role for kinase suppressor of Ras 1 as a positive regulator of neurotensin secretion from human endocrine cells and indicate that this effect is mediated by the extracellular signal-regulated kinase 1 and 2 signaling pathway. (PMID:30917119)
• Praja2 suppresses the growth of gastric cancer by ubiquitylation of KSR1 and inhibiting MEK-ERK signal pathways. (PMID:33461174)
• SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity. (PMID:36493900)
• Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells. (PMID:37511580)
• SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status. (PMID:37972068)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ksr1b	ENSDARG00000030933
danio_rerio	ksr1a	ENSDARG00000068714
mus_musculus	Ksr1	ENSMUSG00000018334
rattus_norvegicus	Ksr1	ENSRNOG00000012818

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Kinase suppressor of Ras 1 — Q8IVT5 (reviewed: Q8IVT5)

All UniProt accessions (8): A0A2R8Y4X0, A0A2R8Y5H9, A8MY87, Q8IVT5, J3QLI1, J3QQL4, J3QR75, J3QSG8

UniProt curated annotations — full annotation on UniProt →

Function. Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases. Independently of its kinase activity, acts as MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or MAP2K2/MEK2. Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP. Its kinase activity is unsure. Some protein kinase activity has been detected in vitro, however the physiological relevance of this activity is unknown.

Subunit / interactions. Homodimer. Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent manner. Interacts with MAP2K1/MEK1 and MAP2K2/MEK2. Binding to MAP2K1/MEK1 releases the intramolecular inhibitory interaction between KSR1 N-terminus and kinase domains which is required for the subsequent RSK1 dimerization with BRAF. Identified in a complex with AKAP13, MAP2K1 and BRAF. Interacts with AKAP13 and BRAF. Interacts with RAF and MAPK/ERK, in a Ras-dependent manner. Interacts with 14-3-3 proteins including YWHAB. Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37. The binding of 14-3-3 proteins to phosphorylated KSR1 prevents the membrane localization. Interacts with MARK3/C-TAK1. Interacts with PPP2R1A and PPP2CA. Interacts with isoform 1 of VRK2.

Subcellular location. Cytoplasm. Membrane. Cell membrane. Cell projection. Ruffle membrane. Endoplasmic reticulum membrane.

Post-translational modifications. Phosphorylated on Ser-311 and, to a higher extent, on Ser-406 by MARK3. Dephosphorylated on Ser-406 by PPP2CA. In resting cells, phosphorylated KSR1 is cytoplasmic and in stimulated cells, dephosphorylated KSR1 is membrane-associated. Phosphorylated by PKA at Ser-888. Phosphorylation at Ser-888 is required for cAMP-dependent activation of MAPK1 and/or MAPK3.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1 and MAP2K2 membrane localization. The domain is required but not sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation. The N-terminal region mediates interaction with BRAF. Also mediates membrane localization.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8IVT5-1	1	yes
Q8IVT5-2	2
Q8IVT5-3	3
Q8IVT5-4	4

RefSeq proteins (5): NP_001354739, NP_001381512, NP_001381513, NP_001381514, NP_055053 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily
IPR046861	SAM_KSR1_N	Domain
IPR046933	SAM_KSR1_N_sf	Homologous_superfamily
IPR050167	Ser_Thr_protein_kinase	Family

Pfam: PF07714, PF20406

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (85 total): helix 23, binding site 11, strand 10, modified residue 9, mutagenesis site 8, compositionally biased region 7, region of interest 6, splice variant 3, sequence variant 3, chain 1, domain 1, active site 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5VYK	X-RAY DIFFRACTION	1.75
9AXH	X-RAY DIFFRACTION	2.81
7JUW	X-RAY DIFFRACTION	2.88
7JUY	X-RAY DIFFRACTION	3.1
7JUZ	X-RAY DIFFRACTION	3.21
7JUX	X-RAY DIFFRACTION	3.34
7JV1	X-RAY DIFFRACTION	3.62
7JV0	X-RAY DIFFRACTION	3.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVT5-F1	61.11	0.17

Functional residue map

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

Catalytic / active sites (1): 733 (proton acceptor)

Ligand- & substrate-binding residues (11): 348; 360; 363; 373; 376; 381; 384; 391; 619–627; 735; 750

Post-translational modifications (9): 270, 274, 311, 334, 351, 406, 425, 569, 888

Mutagenesis-validated functional residues (8):

Position	Phenotype
47	reduces interaction with braf and map2k1 and thus phosphorylation of map2k1.
62	reduces interaction with braf and map2k1 and thus phosphorylation of map2k1.
72	loss of interaction with braf and map2k1 and severe decrease in map2k1 phosphorylation levels.
602–604	no effect on map2k1- or map2k2-mediated-braf-ksr1 dimerization and braf activation.
637	no effect on map2k1 or map2k2 mediated-braf-ksr1 dimerization and braf activation.
639	no effect on map2k1 mediated-braf-ksr1 dimerization and braf activation.
665	loss of map2k1 mediated-braf-ksr1 dimerization.
831	loss of the interaction with map2k1 resulting in loss of braf-ksr1 dimerization and braf activation. no effect on atp bi

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-5673000	RAF activation
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants
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-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802949	Signaling by RAS mutants
R-HSA-6802957	Oncogenic MAPK signaling

MSigDB gene sets: 226 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, PEREZ_TP63_TARGETS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOCC_RUFFLE, RIZKI_TUMOR_INVASIVENESS_3D_DN, chr17q11, BOYLAN_MULTIPLE_MYELOMA_D_DN, KOYAMA_SEMA3B_TARGETS_UP, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, SANSOM_APC_TARGETS_DN, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, PID_CERAMIDE_PATHWAY, PEREZ_TP53_AND_TP63_TARGETS

GO Biological Process (6): Ras protein signal transduction (GO:0007265), regulation of cell population proliferation (GO:0042127), regulation of MAP kinase activity (GO:0043405), positive regulation of MAPK cascade (GO:0043410), MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468)

GO Molecular Function (16): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase scaffold activity (GO:0005078), ATP binding (GO:0005524), zinc ion binding (GO:0008270), 14-3-3 protein binding (GO:0071889), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), protein kinase binding (GO:0019901), mitogen-activated protein kinase kinase binding (GO:0031434), metal ion binding (GO:0046872), protein-folding chaperone binding (GO:0051087), Hsp90 protein binding (GO:0051879)

GO Cellular Component (9): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), ruffle membrane (GO:0032587), protein-containing complex (GO:0032991), plasma membrane (GO:0005886), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Oncogenic MAPK signaling	6
RAF/MAP kinase cascade	3
Signaling by RAS mutants	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	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	4
MAPK cascade	2
protein kinase activity	2
protein binding	2
cytoplasm	2
small GTPase-mediated signal transduction	1
cell population proliferation	1
regulation of cellular process	1
MAP kinase activity	1
regulation of protein serine/threonine kinase activity	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
signaling adaptor activity	1
mitogen-activated protein kinase binding	1
protein complex scaffold activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
kinase binding	1
protein kinase binding	1
cation binding	1
heat shock protein binding	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
ruffle	1

Protein interactions and networks

STRING

1758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KSR1	LSP1	P33241	986
KSR1	RAF1	P04049	982
KSR1	MAP2K1	Q02750	941
KSR1	CNKSR1	Q969H4	895
KSR1	CNKSR2	Q8WXI2	840
KSR1	LAMTOR3	Q9UHA4	815
KSR1	BRAF	P15056	780
KSR1	SHOC2	Q9UQ13	779
KSR1	MAPK3	P27361	764
KSR1	HSP90AA1	P07900	741
KSR1	HSP90AB1	P08238	741
KSR1	RPTOR	Q8N122	704
KSR1	IQGAP1	P46940	701
KSR1	AKAP13	Q12802	699
KSR1	RICTOR	Q6R327	691

IntAct

188 interactions, top by confidence:

A	B	Type	Score
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
MAP2K2	RAF1	psi-mi:“MI:0914”(association)	0.850
KSR1	MAP2K2	psi-mi:“MI:0915”(physical association)	0.800
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
VRK2	KSR1	psi-mi:“MI:0403”(colocalization)	0.650
VRK2	KSR1	psi-mi:“MI:0915”(physical association)	0.650
KSR1	VRK2	psi-mi:“MI:0915”(physical association)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAE	KSR1	psi-mi:“MI:0915”(physical association)	0.600
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
RAF1	KSR1	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
MAP2K2	BAG2	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
EGFL8	MPO	psi-mi:“MI:0914”(association)	0.530
PPP2R2A	KSR1	psi-mi:“MI:0914”(association)	0.530
SFN	KSR1	psi-mi:“MI:0915”(physical association)	0.470
KSR1	EBNA1BP2	psi-mi:“MI:0915”(physical association)	0.400
BRAP	KSR1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (169): KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-Western), KSR1 (Affinity Capture-Western), KSR1 (Affinity Capture-Western), KSR1 (Reconstituted Complex), PJA2 (Affinity Capture-Western), PJA2 (Reconstituted Complex), KSR1 (Biochemical Activity), KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-MS), KSR1 (Affinity Capture-MS)

ESM2 similar proteins: A2AB59, B1AK53, B2DD29, D3YZU1, D3ZG83, O09039, O14976, O54967, O75427, P80192, P98171, Q02779, Q17R13, Q3TBD2, Q3U1V8, Q3UHC7, Q4ACU6, Q4LDD4, Q5DU25, Q5JU85, Q5RB40, Q5RJI5, Q5TCX8, Q5U2X5, Q5VWQ8, Q61097, Q61210, Q66HA1, Q66L42, Q6TLK4, Q6ZUM4, Q80XI6, Q86VW2, Q8IVT5, Q8R0S2, Q8R5F8, Q8R5G7, Q8TDC3, Q8TE68, Q8WWN8

Diamond homologs: A0QNG1, A5TY84, A7E3S4, B5VNQ3, D3ZSZ3, E1BMN8, E2QWQ2, G5EDA5, G5EFD2, O22187, O34507, O54949, O75676, P00531, P04049, P05625, P06244, P0A5S5, P10533, P11345, P11346, P15056, P16056, P27966, P28028, P32023, P32562, P34908, P54737, P54744, P9WI80, P9WI81, Q01887, Q03043, Q04982, Q05101, Q07292, Q10292, Q12469, Q18846

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
MAP3K7	down-regulates	KSR1	phosphorylation
BRAP	“down-regulates quantity by destabilization”	KSR1	ubiquitination
KSR1	“up-regulates activity”	ARAF	binding
KSR1	“up-regulates activity”	BRAF	binding
KSR1	“up-regulates activity”	RAF1	binding
MARK3	“down-regulates activity”	KSR1	phosphorylation
MARK2	“down-regulates activity”	KSR1	phosphorylation
KSR1	up-regulates	RAF1	phosphorylation
NME1	down-regulates	KSR1	phosphorylation
NME1	unknown	KSR1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 179 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	9	50.8×	7e-12
Activation of BAD and translocation to mitochondria	7	44.8×	6e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	39.5×	1e-08
Signaling by GSK3beta mutants	5	32.0×	6e-06
CTNNB1 S33 mutants aren’t phosphorylated	5	32.0×	6e-06
CTNNB1 S37 mutants aren’t phosphorylated	5	32.0×	6e-06
CTNNB1 S45 mutants aren’t phosphorylated	5	32.0×	6e-06
CTNNB1 T41 mutants aren’t phosphorylated	5	32.0×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
insulin-like growth factor receptor signaling pathway	5	15.2×	3e-03
protein targeting	6	13.5×	2e-03
negative regulation of translation	8	9.6×	2e-03
MAPK cascade	8	7.5×	3e-03
intracellular protein localization	9	5.8×	3e-03
protein phosphorylation	11	4.6×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	119
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4858 predictions. Top by Δscore:

Variant	Effect	Δscore
17:27577634:GCC:G	donor_gain	1.0000
17:27583102:TGAGG:T	donor_loss	1.0000
17:27583103:GAGGT:G	donor_loss	1.0000
17:27583104:AGGTG:A	donor_loss	1.0000
17:27583106:G:C	donor_loss	1.0000
17:27592514:A:AG	acceptor_gain	1.0000
17:27592515:A:AG	acceptor_gain	1.0000
17:27592517:CAGT:C	acceptor_loss	1.0000
17:27592518:A:AG	acceptor_gain	1.0000
17:27592519:G:GA	acceptor_gain	1.0000
17:27592519:GT:G	acceptor_gain	1.0000
17:27592519:GTA:G	acceptor_gain	1.0000
17:27592519:GTAA:G	acceptor_gain	1.0000
17:27592519:GTAAC:G	acceptor_gain	1.0000
17:27592623:GAAG:G	donor_gain	1.0000
17:27592624:AAG:A	donor_loss	1.0000
17:27592625:AG:A	donor_loss	1.0000
17:27592626:GG:G	donor_loss	1.0000
17:27592627:G:GC	donor_loss	1.0000
17:27592628:T:G	donor_loss	1.0000
17:27605428:TTTCA:T	acceptor_loss	1.0000
17:27605429:TTCAG:T	acceptor_loss	1.0000
17:27605432:A:AG	acceptor_gain	1.0000
17:27605432:AG:A	acceptor_gain	1.0000
17:27605433:G:GT	acceptor_gain	1.0000
17:27605433:GG:G	acceptor_gain	1.0000
17:27605433:GGC:G	acceptor_gain	1.0000
17:27605433:GGCT:G	acceptor_gain	1.0000
17:27605809:ACCAG:A	donor_loss	1.0000
17:27605810:CCAGG:C	donor_loss	1.0000

AlphaMissense

6061 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001193 (17:27476453 C>T), RS1000011290 (17:27607068 G>T), RS1000014899 (17:27514432 G>A), RS1000016382 (17:27526130 A>G), RS1000023980 (17:27557906 G>A), RS1000041688 (17:27610892 GC>G), RS1000077744 (17:27558157 C>G), RS1000081608 (17:27524612 G>A), RS1000085289 (17:27473108 C>A), RS1000095834 (17:27572183 A>G), RS1000144807 (17:27597715 A>G), RS1000175887 (17:27479029 C>T), RS1000185867 (17:27559454 T>C), RS1000189744 (17:27519428 C>T), RS1000191872 (17:27570636 G>A)

Disease associations

OMIM: gene MIM:601132 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004132_33	Crohn’s disease	3.000000e-08
GCST004609_78	Monocyte percentage of white cells	5.000000e-11
GCST004625_239	Monocyte count	2.000000e-10
GCST005537_26	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	3.000000e-19
GCST005752_50	Systemic lupus erythematosus	5.000000e-06
GCST90002393_513	Monocyte count	1.000000e-20
GCST90002394_518	Monocyte percentage of white cells	1.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1938215 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — RAF family

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.34	IC50	4590	nM	STAUROSPORINE
5.18	IC50	6650	nM	STAUROSPORINE
5.10	IC50	7940	nM	STAUROSPORINE

PubChem BioAssay actives

3 with measured affinity, of 37 total; 1 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
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715303: Inhibition of human KSR1 using KRREILSRRPSYR as substrate by [gamma-33P]-ATP assay	ic50	4.5900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	increases expression, increases methylation	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	decreases methylation, increases methylation	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
clothianidin	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
excavatolide B	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Cisplatin	increases expression	1

ChEMBL screening assays

33 unique, capped per target: 33 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4034357	Binding	Inhibition of KSR1 activation loop (unknown origin) at 10 uM	Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7T9	Ubigene A-549 KSR1 KO	Cancer cell line	Male
CVCL_D8NY	Ubigene HCT 116 KSR1 KO	Cancer cell line	Male
CVCL_D9I4	Ubigene HEK293 KSR1 KO	Transformed cell line	Female
CVCL_E0G8	Ubigene HeLa KSR1 KO	Cancer cell line	Female
CVCL_SV12	HAP1 KSR1 (-) 1	Cancer cell line	Male
CVCL_SV13	HAP1 KSR1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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