KSR2

Summary

KSR2 (kinase suppressor of ras 2, HGNC:18610) is a protein-coding gene on chromosome 12q24.22-q24.23, encoding Kinase suppressor of Ras 2 (Q6VAB6). Location-regulated scaffold connecting MEK to RAF.

Enables protein serine/threonine kinase activity. Predicted to be involved in Ras protein signal transduction; calcium-mediated signaling; and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within positive regulation of MAPK cascade. Predicted to be located in membrane. Predicted to be active in cytosol and plasma membrane.

Source: NCBI Gene 283455 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 432 total — 3 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes
• MANE Select transcript: NM_173598

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18610
Approved symbol	KSR2
Name	kinase suppressor of ras 2
Location	12q24.22-q24.23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25965
Ensembl gene	ENSG00000171435
Ensembl biotype	protein_coding
OMIM	610737
Entrez	283455

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000339824, ENST00000543793, ENST00000545002

RefSeq mRNA: 1 — MANE Select: NM_173598 NM_173598

CCDS: CCDS61250

Canonical transcript exons

ENST00000339824 — 20 exons

Exon	Start	End
ENSE00001364104	117469662	117469795
ENSE00001365320	117761011	117761524
ENSE00001369895	117855428	117855578
ENSE00001605221	117968076	117968990
ENSE00001683671	117453012	117467205
ENSE00001781819	117860291	117860431
ENSE00003477741	117579119	117579202
ENSE00003480926	117539719	117539887
ENSE00003496357	117471191	117471320
ENSE00003514911	117485595	117485691
ENSE00003519321	117524852	117525219
ENSE00003527616	117555169	117555293
ENSE00003540877	117558506	117558573
ENSE00003548583	117527071	117527119
ENSE00003564103	117484416	117484549
ENSE00003572522	117530941	117531013
ENSE00003601789	117582290	117582359
ENSE00003622544	117476464	117476595
ENSE00003666344	117531666	117531707
ENSE00003693367	117667474	117667658

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 95.43.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2305 / max 235.0520, expressed in 367 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133518	1.2745	289
133517	0.3842	108
133522	0.3126	180
133515	0.2916	76
133512	0.2146	77
133519	0.1973	96
133513	0.1504	55
133520	0.1373	70
133516	0.1133	54
133521	0.0877	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	95.43	gold quality
middle temporal gyrus	UBERON:0002771	94.31	gold quality
postcentral gyrus	UBERON:0002581	87.88	gold quality
endothelial cell	CL:0000115	87.63	gold quality
entorhinal cortex	UBERON:0002728	87.05	gold quality
superior frontal gyrus	UBERON:0002661	86.38	gold quality
parietal lobe	UBERON:0001872	85.13	gold quality
primary visual cortex	UBERON:0002436	83.10	gold quality
buccal mucosa cell	CL:0002336	81.16	silver quality
cerebellar vermis	UBERON:0004720	81.15	gold quality
occipital lobe	UBERON:0002021	80.42	gold quality
Brodmann (1909) area 46	UBERON:0006483	80.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.11	silver quality
sperm	CL:0000019	76.68	gold quality
oviduct epithelium	UBERON:0004804	75.88	silver quality
pituitary gland	UBERON:0000007	75.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.79	gold quality
cerebellum	UBERON:0002037	73.74	gold quality
frontal cortex	UBERON:0001870	73.11	gold quality
cerebellar cortex	UBERON:0002129	73.03	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.01	gold quality
cerebellar hemisphere	UBERON:0002245	72.89	gold quality
temporal lobe	UBERON:0001871	72.24	gold quality
cerebral cortex	UBERON:0000956	72.20	gold quality
Ammon’s horn	UBERON:0001954	72.05	gold quality
neocortex	UBERON:0001950	71.64	gold quality
prefrontal cortex	UBERON:0000451	71.40	gold quality
islet of Langerhans	UBERON:0000006	70.61	gold quality
adenohypophysis	UBERON:0002196	70.46	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	70.08	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1083.81
E-HCAD-35	yes	92.01
E-CURD-119	yes	24.41
E-ANND-3	yes	6.80
E-MTAB-7303	no	963.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

572 targeting KSR2, 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-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
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-6798-5P	100.00	65.77	699
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626

Literature-anchored findings (GeneRIF, showing 14)

• hKSR-2, a new member of the KSR family, negatively regulates Cot-mediated MAP kinase and NF-kappaB pathway signaling (PMID:12975377)
• We find that while hKSR-2 blocks MEKK3 activation, it has little to no effect on other members of the MAP3K family, including MEKK4, TAK1, and Ras-Raf, suggesting that its effects are selective. (PMID:16039990)
• These results demonstrate that kinase suppressor of Ras 2 is a direct target of 1,25-dihydroxyvitamin D(3)in HL60 cells, and is required for optimal monocytic differentiation. (PMID:17599832)
• KSR-2 may act as a scaffold protein similar as KSR-1 to mediate the MAPK core (RAF-MEK-ERK) signaling but with a distinct RAF isoform specificity; KSR-2 may only mediate the A-RAF signaling while KSR-1 transduces signals only from c-RAF. (PMID:19563921)
• Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells. (PMID:20945381)
• The involvement of KSR2 in regulation of cell proliferation was predicted by a KSR2-centered network analysis. (PMID:21403620)
• KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK’s phosphorylation by a separate catalytic Raf molecule in trans (PMID:21441910)
• study demonstrated that miR-31 upregulated IL-2 expression via reduction of its up-stream kinase suppressor, KSR2, and is a component of T cell activation (PMID:23303246)
• Study explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells. (PMID:24209692)
• KSR2 deficiency affects stromal interaction molecule 1 (STIM1)/ORAI1 puncta formation, which is correlated with cytoskeleton disorganization. (PMID:24672054)
• These observations suggest that, in the brain, KSR2 regulates energy balance via control of feeding behavior and adaptive thermogenesis, while a second KSR2-dependent mechanism, functioning through one or more other tissues, modulates sensitivity to leptin and activators of the energy sensor AMPK. (PMID:28180061)
• A pleiotropic effect of KSR2-rs7973260 was found on the risk of metabolic syndrome, severe hypertriglyceridemia, and diabetes. (PMID:28537769)
• Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation. (PMID:33040078)
• MiR-3138 deteriorates the insulin resistance of HUVECs via KSR2/AMPK/GLUT4 signaling pathway. (PMID:33509040)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ksr2	ENSDARG00000094526
mus_musculus	Ksr2	ENSMUSG00000061578
rattus_norvegicus	Ksr2	ENSRNOG00000028630

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), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Kinase suppressor of Ras 2 — Q6VAB6 (reviewed: Q6VAB6)

All UniProt accessions (1): Q6VAB6

UniProt curated annotations — full annotation on UniProt →

Function. Location-regulated scaffold connecting MEK to RAF. Has very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency (in vitro). Acts as MAP2K1/MEK1-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1. Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 (in vitro). Blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. Acts as a negative regulator of MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways, inhibiting MAP3K3-mediated interleukin-8 production.

Subunit / interactions. Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1-dependent manner. Interacts with BRAF; this increases the low intrinsic protein kinase activity of KSR2. Interacts with MAP2K1, forming a heterodimer that can dimerize to form a heterotetramer. Interacts with MAP3K8, MAPK, RAS and RAF.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Mainly expressed in brain and kidney.

Post-translational modifications. Phosphorylated on Ser-474 by MARK3.

Activity regulation. Kinase activity is inhibited by ASC24.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive and seems to have very low intrinsic kinase activity. This low kinase activity can be increased by interaction with BRAF.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q6VAB6-1	1	yes
Q6VAB6-2	2

RefSeq proteins (1): NP_775869* (*=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
IPR025561	KSR_SAM-like_dom	Domain
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, PF13543, PF20406

Enzyme classification (BRENDA):

• EC 2.7.11.25 — mitogen-activated protein kinase kinase kinase (BRENDA: 30 organisms, 191 substrates, 74 inhibitors, 12 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MEK	0.0002–0.0004	6
ATP	0.02–0.394	5

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 (60 total): helix 15, binding site 11, strand 11, modified residue 4, splice variant 4, mutagenesis site 3, compositionally biased region 3, region of interest 2, turn 2, chain 1, domain 1, zinc finger region 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7JUR	X-RAY DIFFRACTION	2.82
7JUS	X-RAY DIFFRACTION	2.99
7JUT	X-RAY DIFFRACTION	3.09
7JUU	X-RAY DIFFRACTION	3.19
7JUQ	X-RAY DIFFRACTION	3.22
7UMB	X-RAY DIFFRACTION	3.23
7JUV	X-RAY DIFFRACTION	3.36
2Y4I	X-RAY DIFFRACTION	3.46
5KKR	X-RAY DIFFRACTION	3.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6VAB6-F1	61.22	0.21

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): 786 (proton donor/acceptor)

Ligand- & substrate-binding residues (11): 425; 428; 438; 441; 446; 449; 456; 672–680; 788; 803; 413

Post-translational modifications (4): 272, 276, 474, 497

Mutagenesis-validated functional residues (3):

Position	Phenotype
718	impairs formation of heterotetramers with map2k1, but not the formation of heterodimers.
786	loss of kinase activity.
879	impairs map2k1 binding.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-5674135	MAP2K and MAPK activation
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: 200 (showing top): GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, AP4_Q6, CAGCTG_AP4_Q5, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, KIM_GERMINAL_CENTER_T_HELPER_UP, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, FIRESTEIN_CTNNB1_PATHWAY, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_TEMPERATURE_HOMEOSTASIS, TGGAAA_NFAT_Q4_01, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_HOMEOSTATIC_PROCESS, GOMF_MITOGEN_ACTIVATED_PROTEIN_KINASE_KINASE_BINDING, GOMF_PROTEIN_KINASE_ACTIVITY

GO Biological Process (6): Ras protein signal transduction (GO:0007265), calcium-mediated signaling (GO:0019722), positive regulation of MAPK cascade (GO:0043410), positive regulation of cold-induced thermogenesis (GO:0120162), MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468)

GO Molecular Function (12): 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), mitogen-activated protein kinase kinase binding (GO:0031434), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Oncogenic MAPK signaling	6
RAF/MAP kinase cascade	1
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	3
intracellular signaling cassette	2
MAPK cascade	2
protein kinase activity	2
small GTPase-mediated signal transduction	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	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
protein kinase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KSR2	MAP2K1	Q02750	738
KSR2	BRAF	P15056	477
KSR2	SSMEM1	Q8WWF3	475
KSR2	NAIF1	Q69YI7	473
KSR2	LRGUK	Q96M69	458
KSR2	METTL6	Q8TCB7	457
KSR2	RIT1	Q92963	451
KSR2	SPACA1	Q9HBV2	447
KSR2	TMEM169	Q96HH4	433
KSR2	CREBRF	Q8IUR6	429
KSR2	BBOF1	Q8ND07	423
KSR2	CIB4	A0PJX0	405
KSR2	BCL2L12	Q9HB09	405
KSR2	MAPK3	P27361	390
KSR2	IKBKB	O14920	384

IntAct

26 interactions, top by confidence:

A	B	Type	Score
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
FKBP5	KSR2	psi-mi:“MI:0915”(physical association)	0.670
HSP90AA1	KSR2	psi-mi:“MI:0915”(physical association)	0.670
KSR2	CDC37	psi-mi:“MI:0915”(physical association)	0.670
KSR2	MAP2K2	psi-mi:“MI:0914”(association)	0.640
CYSRT1	KSR2	psi-mi:“MI:0915”(physical association)	0.560
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
HSP90AB1	KSR2	psi-mi:“MI:0915”(physical association)	0.400
BRAF	KSR2	psi-mi:“MI:0915”(physical association)	0.400
KSR2		psi-mi:“MI:0915”(physical association)	0.400
	KSR2	psi-mi:“MI:0915”(physical association)	0.400
FKBP6	KSR2	psi-mi:“MI:0915”(physical association)	0.400
PPP5C	KSR2	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
MAP2K2	IPO5	psi-mi:“MI:0914”(association)	0.350
GPRASP2	GYG2	psi-mi:“MI:0914”(association)	0.350
KSR2	GYG2	psi-mi:“MI:0914”(association)	0.350
KSR2	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (55): KSR2 (Affinity Capture-RNA), KSR2 (Affinity Capture-Western), KSR2 (Affinity Capture-Western), MAP3K8 (Affinity Capture-Western), CYSRT1 (Two-hybrid), KSR2 (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), KSR2 (Affinity Capture-MS), MAP2K1 (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), MAP2K2 (Affinity Capture-MS), TBL1XR1 (Affinity Capture-MS), GYG2 (Affinity Capture-MS), WDR34 (Affinity Capture-MS), YWHAG (Affinity Capture-MS)

ESM2 similar proteins: A2VDU3, A7E3S4, A8XJW8, E9PUQ8, F1QGZ6, O35346, O43318, O54748, P04049, P05625, P09560, P0C8E4, P11345, P11346, P27966, P33886, P34152, P34908, P42331, Q00944, Q04982, Q05397, Q07192, Q07292, Q08BR4, Q16760, Q21029, Q3UVC0, Q56R14, Q5R5M7, Q5RFL3, Q5U2Z7, Q61083, Q61084, Q61097, Q61UC4, Q62073, Q69Z98, Q6GPK9, Q6VAB6

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, A7E3S4, F1LM93, F1RDG9, F4JTP5, G5EFD2, O08680, O09127, O19004, O22558, O45539, P00523, P00524, P00525, P00526, P00527, P00531, P00532, P04049, P04627, P05480, P05625, P06239, P06241, P07947, P07948, P09324, P09560, P09769, P10398, P10533, P10936, P11345, P11346, P12931, P13115, P13116, P13406

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
KSR2	“up-regulates activity”	ARAF	binding
KSR2	“up-regulates activity”	BRAF	binding
KSR2	“up-regulates activity”	RAF1	binding
PPP3CB	“up-regulates activity”	KSR2	dephosphorylation
PPP3CC	“up-regulates activity”	KSR2	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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
Negative regulation of MAPK pathway	5	102.2×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	5	51.1×	2e-06
protein folding	5	34.5×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	210
Likely benign	154
Benign	35

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2634064	NM_173598.6(KSR2):c.1886_1887del (p.Glu629fs)	Likely pathogenic
2636966	NM_173598.6(KSR2):c.1802+2T>A	Likely pathogenic
3352023	NM_173598.6(KSR2):c.1387C>T (p.Arg463Ter)	Likely pathogenic

SpliceAI

5393 predictions. Top by Δscore:

Variant	Effect	Δscore
12:117469659:TACT:T	donor_loss	1.0000
12:117469660:A:AC	donor_gain	1.0000
12:117469660:ACT:A	donor_gain	1.0000
12:117469661:C:CA	donor_gain	1.0000
12:117469661:CT:C	donor_gain	1.0000
12:117469661:CTC:C	donor_gain	1.0000
12:117469661:CTCTG:C	donor_gain	1.0000
12:117469672:T:TA	donor_gain	1.0000
12:117469673:C:A	donor_gain	1.0000
12:117469776:C:CT	acceptor_gain	1.0000
12:117469777:A:T	acceptor_gain	1.0000
12:117476459:CTTA:C	donor_loss	1.0000
12:117476460:TTA:T	donor_loss	1.0000
12:117476461:T:TG	donor_loss	1.0000
12:117476462:A:AC	donor_gain	1.0000
12:117476462:AC:A	donor_gain	1.0000
12:117476462:ACC:A	donor_gain	1.0000
12:117476463:C:CG	donor_gain	1.0000
12:117476463:C:CT	donor_loss	1.0000
12:117476463:CC:C	donor_gain	1.0000
12:117476463:CCC:C	donor_gain	1.0000
12:117476463:CCCA:C	donor_gain	1.0000
12:117476463:CCCAA:C	donor_gain	1.0000
12:117476505:AT:A	donor_gain	1.0000
12:117476505:ATCCT:A	donor_gain	1.0000
12:117476592:CCGC:C	acceptor_gain	1.0000
12:117476593:CGCC:C	acceptor_gain	1.0000
12:117484411:CTCA:C	donor_loss	1.0000
12:117484412:TCA:T	donor_loss	1.0000
12:117484414:ACCT:A	donor_loss	1.0000

AlphaMissense

6257 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:117469690:G:C	H940D	1.000
12:117469692:G:A	S939F	1.000
12:117469701:C:G	R936P	1.000
12:117469702:G:A	R936C	1.000
12:117469702:G:C	R936G	1.000
12:117469702:G:T	R936S	1.000
12:117469716:A:G	L931P	1.000
12:117469754:T:A	R918S	1.000
12:117469754:T:G	R918S	1.000
12:117469755:C:G	R918T	1.000
12:117469777:A:G	W911R	1.000
12:117469777:A:T	W911R	1.000
12:117469780:A:G	C910R	1.000
12:117469788:A:G	L907P	1.000
12:117471303:A:G	L867P	1.000
12:117471313:A:G	W864R	1.000
12:117471313:A:T	W864R	1.000
12:117476464:C:T	G861D	1.000
12:117476465:C:G	G861R	1.000
12:117476470:G:T	A859D	1.000
12:117476480:C:A	D856Y	1.000
12:117476480:C:G	D856H	1.000
12:117476551:A:G	L832P	1.000
12:117476564:A:G	W828R	1.000
12:117476564:A:T	W828R	1.000
12:117484452:C:T	G805E	1.000
12:117484453:C:G	G805R	1.000
12:117484453:C:T	G805R	1.000
12:117484454:A:C	F804L	1.000
12:117484454:A:T	F804L	1.000

dbSNP variants (sampled 300 via entrez): RS1000001009 (12:117667403 G>C), RS1000018219 (12:117627583 T>C), RS1000034841 (12:117881096 C>T), RS1000044142 (12:117752040 A>C), RS1000050481 (12:117593557 T>C), RS1000059790 (12:117874022 C>T), RS1000060481 (12:117962608 C>T), RS1000075364 (12:117839650 A>G), RS1000075832 (12:117956399 C>A,T), RS1000076415 (12:117921490 C>T), RS1000078759 (12:117633595 T>C), RS1000080405 (12:117833467 A>G), RS1000092287 (12:117587558 A>C), RS1000096237 (12:117486637 T>C,G), RS1000101526 (12:117793540 C>A,T)

Disease associations

OMIM: gene MIM:610737 | disease phenotypes: MIM:125853, MIM:209850

GenCC curated gene-disease

Mondo (6): diabetes mellitus (MONDO:0005015), hypertensive disorder (MONDO:0005044), type 2 diabetes mellitus (MONDO:0005148), obesity disorder (MONDO:0011122), hyperlipidemia (MONDO:0021187), autism (MONDO:0005260)

Orphanet (2): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0001513	Obesity
HP:0003077	Hyperlipidemia
HP:0000717	Autism

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000328_1	Biochemical measures	6.000000e-06
GCST000328_7	Biochemical measures	6.000000e-07
GCST001523_5	Visceral adipose tissue adjusted for BMI	8.000000e-06
GCST001894_14	Endometriosis	7.000000e-06
GCST003116_9	Coronary artery disease	2.000000e-09
GCST003262_365	Post bronchodilator FEV1	1.000000e-06
GCST003264_1594	Post bronchodilator FEV1/FVC ratio	6.000000e-09
GCST003769_6	Depression	2.000000e-08
GCST003815_105	Late-onset Alzheimer’s disease	6.000000e-06
GCST004105_6	Body mass index (change over time) in chronic obstructive pulmonary disease	8.000000e-06
GCST005024_81	Pursuit maintenance gain	3.000000e-07
GCST005028_9	Pursuit maintenance gain in psychotic disorders	2.000000e-07
GCST007847_121	Type 2 diabetes	2.000000e-08
GCST008129_57	Body mass index	1.000000e-08
GCST008156_77	Hip circumference adjusted for BMI	5.000000e-06
GCST008180_4	Spontaneous preterm birth with premature rupture of membranes	2.000000e-06
GCST008477_4	Emphysema annual change measurement in smokers (adjusted lung density)	7.000000e-06
GCST009379_345	Type 2 diabetes	2.000000e-09
GCST009379_346	Type 2 diabetes	2.000000e-06
GCST010002_175	Refractive error	8.000000e-14
GCST010118_88	Type 2 diabetes	2.000000e-15
GCST010989_50	Body size at age 10	2.000000e-12
GCST011494_61	Daytime nap	2.000000e-87
GCST012481_10	Cerebral amyloid angiopathy in Alzheimer’s disease	6.000000e-06

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004340	body mass index
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0007006	depressive symptom measurement
EFO:1001870	late-onset Alzheimers disease
EFO:0005937	longitudinal BMI measurement
EFO:0008433	pursuit maintenance gain measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0006917	spontaneous preterm birth
EFO:0007626	emphysema imaging measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007828	daytime rest measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D003920	Diabetes Mellitus	C18.452.394.750; C19.246
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D006949	Hyperlipidemias	C18.452.584.500.500
D006973	Hypertension	C14.907.489

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3627583 (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
5.43	IC50	3730	nM	STAUROSPORINE
5.40	IC50	3980	nM	STAUROSPORINE
5.17	IC50	6820	nM	STAUROSPORINE

PubChem BioAssay actives

3 with measured affinity, of 29 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	2198284: Inhibition of human KSR2 using KRREILSRRPSYR as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	3.7300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
ATP-biotin	affects binding, decreases reaction	1
bisphenol F	increases methylation	1
APS-2-79	affects binding, decreases reaction	1
propionaldehyde	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	decreases expression, affects cotreatment	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects methylation	1
Methapyrilene	decreases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3631907	Binding	Inhibition of KSR2 (unknown origin) at 10 uM after 120 mins P33 radiolabeled kinase activity assay	Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7TA	Ubigene A-549 KSR2 KO	Cancer cell line	Male
CVCL_D8NZ	Ubigene HCT 116 KSR2 KO	Cancer cell line	Male
CVCL_SV14	HAP1 KSR2 (-) 1	Cancer cell line	Male
CVCL_SV15	HAP1 KSR2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00044746	PHASE4	COMPLETED	Study Evaluating the Safety and Efficacy of Piperacillin/Tazobactam and Ampicillin/Sulbactam in Patients With Diabetic Foot Infections
NCT00069602	PHASE4	COMPLETED	Assessing Continuous Glucose Monitors in Healthy Children
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00108615	PHASE4	COMPLETED	Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
NCT00117780	PHASE4	COMPLETED	Comparison of Insulin Detemir Given Once or Twice Daily in Type 1 Diabetes
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy
NCT00121355	PHASE4	COMPLETED	Novofine Autocover Safety Needle Versus BD Safety Glide
NCT00135226	PHASE4	ACTIVE_NOT_RECRUITING	ASCEND: A Study of Cardiovascular Events iN Diabetes
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	PHASE4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00162344	PHASE4	COMPLETED	A Study of Stress Heart Imaging in Patients With Diabetes at Risk for Coronary Disease.
NCT00177138	PHASE4	TERMINATED	Use of Campath for Induction and Maintenance Therapy in Pancreas After Kidney Transplantation
NCT00182494	PHASE4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00202618	PHASE4	UNKNOWN	Rationale and Design for Shiga Microalbuminuria Reduction Trial
NCT00209170	PHASE4	COMPLETED	Depression-Diabetes Mechanisms: Urban African Americans
NCT00209417	PHASE4	TERMINATED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Computed Tomography
NCT00212004	PHASE4	TERMINATED	Pioglitazone Protects Diabetes Mellitus (DM) Patients Against Re-Infarction (PPAR Study)
NCT00219440	PHASE4	COMPLETED	A Portion-controlled Diet Will Prevent Weight Gain in Diabetics Treated With ACTOS
NCT00225849	PHASE4	UNKNOWN	Japanese Primary Prevention Project With Aspirin
NCT00231894	PHASE4	COMPLETED	Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00235014	PHASE4	COMPLETED	A Study for Prevention of Kidney Disease in Diabetic Patients (BENEDICT)
NCT00236379	PHASE4	COMPLETED	A Study of the Effects of Risperidone and Olanzapine on Blood Glucose (Sugar) in Patients With Schizophrenia or Schizoaffective Disorder
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community
NCT00263393	PHASE4	COMPLETED	Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS)
NCT00264901	PHASE4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00274274	PHASE4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00282451	PHASE4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00282659	PHASE4	COMPLETED	The Use of Magnesium to Improve Blood Pressure, Cholesterol, and Glucose Control
NCT00287820	PHASE4	COMPLETED	Comparative Effects of Chronic Treatment With Olanzapine and Risperidone on Glucose and Lipid Metabolism
NCT00295555	PHASE4	COMPLETED	Doxazosin Effects on ABPM in Hypertensive Patients With Diabetic Nephropathy
NCT00299169	PHASE4	TERMINATED	Randomized Trial Comparing N of 1 Trials to Standard Practice to Improve Adherence to Statins in Patients With Diabetes
NCT00301392	PHASE4	COMPLETED	Japan Prevention Trial of Diabetes by Pitavastatin in Patients With Impaired Glucose Tolerance (J-PREDICT)
NCT00306696	PHASE4	COMPLETED	Examining the Effect of Different Diuretics on Fluid Retention in Diabetics Treated With Rosiglitazone.
NCT00309465	PHASE4	COMPLETED	Perioperative Insulin Glargine Dosing Study