CRTC2

Summary

CRTC2 (CREB regulated transcription coactivator 2, HGNC:27301) is a protein-coding gene on chromosome 1q21.3, encoding CREB-regulated transcription coactivator 2 (Q53ET0). Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites.

This gene encodes a member of the transducers of regulated cAMP response element-binding protein activity family of transcription coactivators. These proteins promote the transcription of genes targeted by the cAMP response element-binding protein, and therefore play an important role in many cellular processes. Under basal conditions the encoded protein is phosphorylated by AMP-activated protein kinase or the salt-inducible kinases and is sequestered in the cytoplasm. Upon activation by elevated cAMP or calcium, the encoded protein translocates to the nucleus and increases target gene expression. Single nucleotide polymorphisms in this gene may increase the risk of type 2 diabetes. A pseudogene of this gene is located on the long arm of chromosome 5.

Source: NCBI Gene 200186 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 107 total
• MANE Select transcript: NM_181715

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27301
Approved symbol	CRTC2
Name	CREB regulated transcription coactivator 2
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	TORC2
Ensembl gene	ENSG00000160741
Ensembl biotype	protein_coding
OMIM	608972
Entrez	200186

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000303569, ENST00000368630, ENST00000368633, ENST00000461638, ENST00000467860, ENST00000476883, ENST00000487235, ENST00000492073, ENST00000493909, ENST00000524997, ENST00000870599, ENST00000917166, ENST00000917167, ENST00000917168, ENST00000917169, ENST00000956358, ENST00000956359, ENST00000956360

RefSeq mRNA: 1 — MANE Select: NM_181715 NM_181715

CCDS: CCDS30875

Canonical transcript exons

ENST00000368633 — 14 exons

Exon	Start	End
ENSE00001447633	153958345	153958612
ENSE00003465863	153953538	153953606
ENSE00003470432	153954873	153954989
ENSE00003546651	153952571	153952635
ENSE00003554424	153948458	153948644
ENSE00003556347	153954255	153954316
ENSE00003560358	153955065	153955166
ENSE00003574867	153951260	153951666
ENSE00003611725	153952805	153952834
ENSE00003629770	153947675	153948329
ENSE00003643050	153952018	153952262
ENSE00003648444	153949115	153949384
ENSE00003674498	153952397	153952446
ENSE00003675930	153953266	153953369

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 96.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.8846 / max 351.5060, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14744	23.3879	1804
14743	0.4967	278

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.89	gold quality
left ovary	UBERON:0002119	96.29	gold quality
right ovary	UBERON:0002118	96.09	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.94	gold quality
right lung	UBERON:0002167	95.89	gold quality
spleen	UBERON:0002106	95.83	gold quality
right lobe of thyroid gland	UBERON:0001119	95.75	gold quality
cerebellar hemisphere	UBERON:0002245	95.73	gold quality
left lobe of thyroid gland	UBERON:0001120	95.72	gold quality
cerebellar cortex	UBERON:0002129	95.66	gold quality
endocervix	UBERON:0000458	95.64	gold quality
body of uterus	UBERON:0009853	95.61	gold quality
lower esophagus mucosa	UBERON:0035834	95.43	gold quality
tibial nerve	UBERON:0001323	95.36	gold quality
upper lobe of left lung	UBERON:0008952	95.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.18	gold quality
right uterine tube	UBERON:0001302	95.11	gold quality
mucosa of stomach	UBERON:0001199	95.09	gold quality
metanephros cortex	UBERON:0010533	95.07	gold quality
skin of leg	UBERON:0001511	94.91	gold quality
minor salivary gland	UBERON:0001830	94.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.61	gold quality
skin of abdomen	UBERON:0001416	94.57	gold quality
adenohypophysis	UBERON:0002196	94.57	gold quality
ectocervix	UBERON:0012249	94.56	gold quality
right lobe of liver	UBERON:0001114	94.45	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.44	gold quality
lymph node	UBERON:0000029	94.35	gold quality
body of stomach	UBERON:0001161	94.33	gold quality
thyroid gland	UBERON:0002046	94.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.44

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
G6PC1	Activation
PCK1	Activation
TSC22D3	Activation

Upstream regulators (CollecTRI, top): ATF6, NR0B2, TCF7L2

miRNA regulators (miRDB)

36 targeting CRTC2, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-583	98.71	67.44	1791

Literature-anchored findings (GeneRIF, showing 32)

• Thus, both TORC1/2 and p300 families of coactivators are essential for optimal activation of HTLV-1 transcription by Tax. (PMID:16809310)
• These results strongly suggest that TORCs play a key role in linking these external signals to the transcriptional program of adaptive mitochondrial biogenesis by activating PGC-1alpha gene transcription. (PMID:16980408)
• latent cytoplasmic coactivator TORC2 mediates target gene activation in response to cAMP signaling by associating with CBP/p300 and increasing its recruitment to a subset of CREB target genes (PMID:17476304)
• TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation. (PMID:17548807)
• genetic variants of LKB1-AMPK-TORC2 pathway components may exert a weak influence on the occurrence of type 2 diabetes in Japanese (PMID:17950019)
• identify Ser-275 of TORC2 as a 14-3-3 binding site that is phosphorylated under low glucose conditions and which becomes dephosphorylated by calcineurin in response to glucose influx (PMID:18626018)
• TORC2, a coactivator of cAMP-response element-binding protein, promotes Epstein-Barr virus reactivation from latency through interaction with viral BZLF1 protein. (PMID:19164291)
• The regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer. (PMID:19509226)
• Tax binds the cyclin D1 promoter-proximal cyclic AMP response element (CRE) in the presence of phosphorylated CREB (pCREB) in vitro, and together the Tax-pCREB complex recruits the cellular co-activator p300 to the promoter. (PMID:20101207)
• the association of Pin1 with CRTC2 to decrease the nuclear CBP.CRTC.CREB complex. (PMID:20675384)
• The lipogenic effects of GIP in the presence of insulin are therefore at least partially mediated by upregulation of adipocyte LPL gene transcription through a pathway involving PI3-K/PKB/AMPK-dependent CREB/TORC2 activation. (PMID:20693566)
• Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2 (PMID:23213254)
• Phosphorylation of CRTC2 at its AMPK target site, Ser 171, dictated its subcellular localization, and the activation of aromatase PII in preadipocytes. (PMID:23584792)
• CRTC2 enhances CREB phosphorylation through an association with the protein arginine methyltransferase 5 (PRMT5). (PMID:23671120)
• The data from the current study demonstrated novel PROM1 and CRTC2 mutations, which could promote lung cancer development. (PMID:24484648)
• These results clearly indicate that non-phosphorylated CRTC2 strongly enhances hepatitis b virus biosynthesis through inducing PGC1alpha expression. (PMID:24529027)
• the high expression of CRTC2 and PROM1 may play an important role in the occurrence and hereditary, and also advance the potential pathways that integrate genetic variants in the development of NSCLC. (PMID:25256670)
• Our results establish a role for CRTC2 as a lymphoma tumor suppressor gene (PMID:26004186)
• CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in transplant recipients after solid organ transplantation. (PMID:26644205)
• CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. (PMID:26652733)
• Thyroid stimulating hormone activates CRTC2 via the TSHR/cAMP/PKA pathway. (PMID:28212844)
• Study suggests that Creb/Crtc2 negatively regulates the Sirt1/Pparalpha/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions. (PMID:29192248)
• Data report crystal structures of a complex containing the CRTC2 CREB binding domain, the CREB basic leucine zipper domain and a CRE-containing DNA. The structures revealed that CRTC and CREB form a 2:2 complex on CRE-containing DNA, and CRTC interacts with both CREB and DNA through highly conserved residues. (PMID:29733854)
• Results identified CRTC2 as a downstream substrate of constitutively activated p38. Constitutive, rather than transient, activation of p38 led to hyperphosphorylation of CRTC2, resulting in CRTC2 cytosolic relocation and subsequent inactivation of cyclic AMP response element (CRE)-mediated transcription. (PMID:30782776)
• CRTC2 is unphosphorylated and therefore constitutively activated in LKB1-mutant non-small cell lung cance, where it promotes tumor growth, in part via the induction of the inhibitor of DNA binding 1. (PMID:31355336)
• Phosphorylation of CREB-Specific Coactivator CRTC2 at Ser238 Promotes Proliferation, Migration, and Invasion of Colorectal Cancer Cells. (PMID:33000695)
• SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells. (PMID:33013689)
• The CREB Regulated Transcription Coactivator 2 Suppresses HIV-1 Transcription by Preventing RNA Pol II from Binding to HIV-1 LTR. (PMID:33723808)
• TORC2/3-mediated DUSP1 upregulation is essential for human decidualization. (PMID:33780908)
• Sam68 promotes hepatic gluconeogenesis via CRTC2. (PMID:34099657)
• cAMP-Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease. (PMID:35037420)
• Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer. (PMID:35504112)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000110500
mus_musculus	Crtc2	ENSMUSG00000027936
rattus_norvegicus	Crtc2	ENSRNOG00000056337
drosophila_melanogaster	Crtc	FBGN0036746
caenorhabditis_elegans	crtc-1	WBGENE00021237

Paralogs (2): CRTC1 (ENSG00000105662), CRTC3 (ENSG00000140577)

Protein

Protein identifiers

CREB-regulated transcription coactivator 2 — Q53ET0 (reviewed: Q53ET0)

Alternative names: Transducer of regulated cAMP response element-binding protein 2

All UniProt accessions (4): Q53ET0, H0YDQ8, J3KNE6, Q5T4K5

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites. Acts as a coactivator, in the SIK/TORC signaling pathway, being active when dephosphorylated and acts independently of CREB1 ‘Ser-133’ phosphorylation. Enhances the interaction of CREB1 with TAF4. Regulates gluconeogenesis as a component of the LKB1/AMPK/TORC2 signaling pathway. Regulates the expression of specific genes such as the steroidogenic gene, StAR. Potent coactivator of PPARGC1A and inducer of mitochondrial biogenesis in muscle cells. Also coactivator for TAX activation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeats (LTR).

Subunit / interactions. Binds, as a tetramer, through its N-terminal region, with the bZIP domain of CREB1. ‘Arg-314’ in the bZIP domain of CREB1 is essential for this interaction. Interaction, via its C-terminal, with TAF4, enhances recruitment of TAF4 to CREB1. Interacts with SIK2. Interacts with 14-3-3 proteins, YWHAB and YWHAG. Interacts (probably when phosphorylated at Ser-171) with YWHAE. Interacts with calmodulin-dependent catalytic subunit PPP3CA/calcineurin A. Interaction with COP1 mediates nuclear export and degradation of CRTC2. (Microbial infection) Interaction with the human T-cell leukemia virus type 1 (HTLV-1) Tax protein is essential for optimal transcription activation by Tax.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Most abundantly expressed in the thymus. Present in both B and T-lymphocytes. Highly expressed in HEK293T cells and in insulinomas. High levels also in spleen, ovary, muscle and lung, with highest levels in muscle. Lower levels found in brain, colon, heart, kidney, prostate, small intestine and stomach. Weak expression in liver and pancreas.

Post-translational modifications. Phosphorylation/dephosphorylation states of Ser-171 are required for regulating transduction of CREB activity. CRTCs/TORCs are inactive when phosphorylated, and active when dephosphorylated at this site. This primary site of phosphorylation, is regulated by cAMP and calcium levels and is dependent on the phosphorylation of SIKs (SIK1 and SIK2) by LKB1. Following adenylyl cyclase activation, dephosphorylated at Ser-171 by PPP3CA/calcineurin A resulting in CRTC2 dissociation from 14-3-3 proteins and PPP3CA. Both insulin and AMPK increase this phosphorylation of CRTC2 while glucagon suppresses it. Phosphorylation at Ser-274 by MARK2 is induced under low glucose conditions and dephosphorylated in response to glucose influx. Phosphorylation at Ser-274 promotes interaction with 14-3-3 proteins and translocation to the cytoplasm. Asymmetric dimethylation of arginine resisues by PRMT6 enhances the association of CRTC2 with CREB on the promoters of gluconeogenic genes.

Polymorphism. Variant Cys-379, under a dominant model, linked to a recessive mutation in LKB1, may be associated with susceptibility to type II or non-insulin-dependent diabetes mellitus (NIDDM).

Similarity. Belongs to the TORC family.

RefSeq proteins (1): NP_859066* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024783	TORC_N	Domain
IPR024784	TORC_M	Domain
IPR024785	TORC_C	Domain
IPR024786	TORC	Family

Pfam: PF12884, PF12885, PF12886

UniProt features (52 total): modified residue 28, compositionally biased region 6, mutagenesis site 5, region of interest 3, sequence variant 2, sequence conflict 2, initiator methionine 1, chain 1, site 1, cross-link 1, short sequence motif 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4HTM	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53ET0-F1	48.89	0.05

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): 629 (required for ubiquitination and degradation)

Post-translational modifications (29): 2, 51, 70, 86, 90, 99, 120, 123, 136, 161, 168, 169, 171, 192, 274, 306, 368, 393, 433, 456 …

Mutagenesis-validated functional residues (5):

Position	Phenotype
70	no effect on camp- and calcium-regulated phosphorylation.
171	loss of camp- and calcium-regulated phosphorylation. greatly reduced interaction with 14-3-3 proteins. impaired phosphor
274	impaired phosphorylation under low glucose conditions and impaired interaction with 14-3-3 proteins; when associated wit
368	reduced camp- and calcium-regulated phosphorylation.
393	no effect on camp- and calcium-regulated phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2

MSigDB gene sets: 162 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_POSITIVE_REGULATION_OF_CREB_TRANSCRIPTION_FACTOR_ACTIVITY, MAZ_Q6, TATTATA_MIR374, AACYNNNNTTCCS_UNKNOWN, FOXO4_01, FOXO1_01, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, NFKB_Q6, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_RESPONSE_TO_CAMP, GOBP_MONOSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_CAMP

GO Biological Process (6): gluconeogenesis (GO:0006094), obsolete positive regulation of CREB transcription factor activity (GO:0032793), glucose homeostasis (GO:0042593), positive regulation of transcription by RNA polymerase II (GO:0045944), protein homotetramerization (GO:0051289), cellular response to cAMP (GO:0071320)

GO Molecular Function (3): transcription coactivator activity (GO:0003713), cAMP response element binding protein binding (GO:0008140), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Cellular responses to stress	1
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
cellular anatomical structure	2
glucose metabolic process	1
hexose biosynthetic process	1
carbohydrate homeostasis	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
protein homooligomerization	1
protein tetramerization	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
transcription coregulator activity	1
DNA-binding transcription factor binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRTC2	CREB1	P16220	997
CRTC2	CREBBP	Q92793	898
CRTC2	PPARGC1A	Q9UBK2	870
CRTC2	NONO	P30807	812
CRTC2	SIK2	Q9H0K1	807
CRTC2	FOXO1	Q12778	794
CRTC2	SIRT1	Q96EB6	789
CRTC2	GCG	P01275	753
CRTC2	ATF6	P18850	744
CRTC2	EP300	Q09472	729
CRTC2	OGA	O60502	688
CRTC2	KAT2B	Q92831	684
CRTC2	G6PC1	P35575	679
CRTC2	SIK1	P57059	668
CRTC2	INS	P01308	657

IntAct

88 interactions, top by confidence:

A	B	Type	Score
CRTC2	YWHAB	psi-mi:“MI:0915”(physical association)	0.890
YWHAB	CRTC2	psi-mi:“MI:0914”(association)	0.890
YWHAG	CRTC2	psi-mi:“MI:0915”(physical association)	0.840
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
MEIS1	CREB1	psi-mi:“MI:0914”(association)	0.680
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
CRTC2	PPP3CC	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	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
CRTC2	SUFU	psi-mi:“MI:0915”(physical association)	0.560
CREB1	CRTC2	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	CRTC2	psi-mi:“MI:0915”(physical association)	0.560
CRTC2	CDC23	psi-mi:“MI:0915”(physical association)	0.560
CRTC2	ATPAF2	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
	CRTC2	psi-mi:“MI:0915”(physical association)	0.560
	CRTC2	psi-mi:“MI:0403”(colocalization)	0.560
CRTC2	NONO	psi-mi:“MI:0915”(physical association)	0.540
CRTC2	NONO	psi-mi:“MI:0407”(direct interaction)	0.540
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (99): CRTC2 (Affinity Capture-MS), CRTC2 (Affinity Capture-MS), CRTC2 (Affinity Capture-MS), CRTC2 (Affinity Capture-MS), CRTC2 (Affinity Capture-Western), PPP3CA (Affinity Capture-Western), CRTC2 (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAE (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), CRTC2 (Affinity Capture-MS), CRTC2 (Affinity Capture-MS)

ESM2 similar proteins: A0JNC2, A1KXE4, A8E639, A8MV65, D4AEP3, E3X5D6, P05411, P12981, P18870, P54864, P60486, Q08BY2, Q0IHC4, Q0VFP2, Q14157, Q15032, Q15038, Q157S1, Q16656, Q3LRZ1, Q3T0A9, Q3T0K9, Q3U182, Q4R5H7, Q53ET0, Q58D45, Q5BJ83, Q5R526, Q5RDV6, Q5U2U6, Q5XIH2, Q5ZIS9, Q68ED7, Q6PEH8, Q7PXU6, Q80TM6, Q80X50, Q80XQ8, Q8AVW3, Q8BGZ2

Diamond homologs: Q08E26, Q0IHT3, Q157S1, Q3LRZ1, Q3U182, Q52KS4, Q53ET0, Q68ED7, Q6UUV7, Q6UUV9, Q91X84, Q95XA8

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
PRKAA2	down-regulates	CRTC2	phosphorylation
metformin	down-regulates	CRTC2
SIK2	down-regulates	CRTC2	phosphorylation
SIK1	down-regulates	CRTC2	phosphorylation
PRKAA1	down-regulates	CRTC2	phosphorylation
AMPK	down-regulates	CRTC2	phosphorylation
SIK1	“down-regulates activity”	CRTC2	phosphorylation
SIK3	“down-regulates activity”	CRTC2	phosphorylation
CRTC2	“up-regulates activity”	NR3C1	binding
CRTC2	“up-regulates activity”	CREB1	binding
CRTC2	“up-regulates quantity”	G6PC1	“transcriptional regulation”
CRTC2	“up-regulates quantity”	PCK1	“transcriptional regulation”
CRTC2	“up-regulates quantity”	TSC22D3	“transcriptional regulation”
CRTC2	“up-regulates quantity”	G6P	“transcriptional regulation”
“DCX DET1-COP1”	“down-regulates quantity by destabilization”	CRTC2	ubiquitination
TRAF6	“down-regulates quantity”	CRTC2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 62 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
Activation of BAD and translocation to mitochondria	7	126.9×	1e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	96.0×	2e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	96.0×	2e-09
Activation of BH3-only proteins	6	70.9×	1e-08
RHO GTPases activate PKNs	6	45.3×	2e-07
Intrinsic Pathway for Apoptosis	6	41.8×	2e-07
FOXO-mediated transcription	5	40.0×	4e-06
Transcriptional and post-translational regulation of MITF-M expression and activity	7	29.7×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	40.0×	4e-06
intracellular protein localization	8	15.2×	1e-05
protein phosphorylation	6	7.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1875 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153948327:CCC:C	acceptor_gain	1.0000
1:153948328:CCC:C	acceptor_gain	1.0000
1:153952258:AGATG:A	acceptor_gain	1.0000
1:153952259:GATG:G	acceptor_gain	1.0000
1:153952260:ATG:A	acceptor_gain	1.0000
1:153952261:TG:T	acceptor_gain	1.0000
1:153952263:C:CC	acceptor_gain	1.0000
1:153952392:CTTA:C	donor_gain	1.0000
1:153952394:TAC:T	donor_loss	1.0000
1:153952395:A:AC	donor_gain	1.0000
1:153952395:ACTTA:A	donor_loss	1.0000
1:153952396:C:CT	donor_gain	1.0000
1:153952396:CT:C	donor_gain	1.0000
1:153952396:CTT:C	donor_gain	1.0000
1:153952396:CTTA:C	donor_gain	1.0000
1:153952396:CTTAA:C	donor_gain	1.0000
1:153952399:AATT:A	donor_gain	1.0000
1:153952442:GATAG:G	acceptor_gain	1.0000
1:153952443:ATAG:A	acceptor_gain	1.0000
1:153952444:TAG:T	acceptor_gain	1.0000
1:153952444:TAGCT:T	acceptor_loss	1.0000
1:153952445:AG:A	acceptor_gain	1.0000
1:153952445:AGCTG:A	acceptor_loss	1.0000
1:153952446:GCTGA:G	acceptor_loss	1.0000
1:153952447:C:CA	acceptor_loss	1.0000
1:153952447:C:CC	acceptor_gain	1.0000
1:153952637:T:C	acceptor_gain	1.0000
1:153954328:CAGT:C	acceptor_gain	1.0000
1:153954329:A:T	acceptor_gain	1.0000
1:153954331:T:C	acceptor_gain	1.0000

AlphaMissense

4439 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153958415:A:G	L28P	1.000
1:153958432:A:C	F22L	1.000
1:153958432:A:T	F22L	1.000
1:153958433:A:C	F22C	1.000
1:153958433:A:G	F22S	1.000
1:153958434:A:G	F22L	1.000
1:153958378:G:C	F40L	0.999
1:153958378:G:T	F40L	0.999
1:153958379:A:C	F40C	0.999
1:153958379:A:G	F40S	0.999
1:153958380:A:G	F40L	0.999
1:153958398:C:G	A34P	0.999
1:153958403:C:G	R32P	0.999
1:153958406:T:G	Q31P	0.999
1:153958419:C:G	A27P	0.999
1:153958421:A:C	I26S	0.999
1:153958427:T:A	E24V	0.999
1:153953347:G:C	H176D	0.998
1:153953358:T:A	D172V	0.998
1:153958386:C:G	A38P	0.998
1:153958421:A:T	I26N	0.998
1:153958423:C:A	K25N	0.998
1:153958423:C:G	K25N	0.998
1:153958429:A:C	S23R	0.998
1:153958429:A:T	S23R	0.998
1:153958431:T:G	S23R	0.998
1:153958440:G:T	R20S	0.998
1:153952182:A:G	L278P	0.997
1:153953339:A:C	S178R	0.997
1:153953339:A:T	S178R	0.997

dbSNP variants (sampled 300 via entrez): RS1000206542 (1:153954165 A>G), RS1000295427 (1:153950375 C>T), RS1000342252 (1:153954707 G>T), RS1000542486 (1:153955798 G>A), RS1000595720 (1:153948499 T>C,G), RS1000678313 (1:153956124 C>G,T), RS1000889511 (1:153949157 T>A), RS1001588165 (1:153947776 G>A,C), RS1002700948 (1:153958803 G>A), RS1002760798 (1:153951858 G>C,T), RS1004438737 (1:153950440 A>C), RS1004687785 (1:153958613 G>A,T), RS1004717116 (1:153956196 C>T), RS1004779778 (1:153957822 C>A,T), RS1004780295 (1:153948833 C>A,T)

Disease associations

OMIM: gene MIM:608972 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST003795_1	Age at first birth	6.000000e-10
GCST005751_3	Empathy quotient	3.000000e-07
GCST006044_1	Age at first birth	3.000000e-07
GCST006045_3	Age at first birth	5.000000e-06
GCST010136_18	Fruit consumption	3.000000e-08
GCST010137_3	Cooked vegetable consumption	3.000000e-09
GCST010138_14	Raw vegetable consumption	5.000000e-11
GCST010142_60	Fish- and plant-related diet	4.000000e-09
GCST010142_92	Fish- and plant-related diet	6.000000e-14
GCST010696_22	Cortical thickness (min-P)	4.000000e-10
GCST010697_50	Cortical surface area (min-P)	1.000000e-12
GCST010698_81	Subcortical volume (min-P)	1.000000e-23
GCST010699_7	Brain morphology (min-P)	1.000000e-10
GCST010700_11	Cortical thickness (MOSTest)	4.000000e-13
GCST010701_73	Cortical surface area (MOSTest)	4.000000e-09
GCST010702_45	Subcortical volume (MOSTest)	4.000000e-10
GCST010703_276	Brain morphology (MOSTest)	2.000000e-15
GCST90000050_7	Age at first birth	4.000000e-14

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009101	age at first birth measurement
EFO:0009183	empathy measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs8450	Toxicity	3	cyclosporine;tacrolimus	Transplantation

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8450	CRTC2, DENND4B	3	5.25	1	cyclosporine;tacrolimus
rs12117078	CRTC2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Caffeine	affects phosphorylation, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
moringin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
ginsenoside Rg2	decreases activity, increases activity	1
epigallocatechin gallate	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
PP242	decreases activity	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Glyphosate	increases expression	1
Cadmium	decreases expression, increases abundance	1
Cannabidiol	affects cotreatment, increases expression	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	decreases expression	1
Copper	affects binding, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8JC	Ubigene HCT 116 CRTC2 KO	Cancer cell line	Male
CVCL_E0B1	Ubigene HeLa CRTC2 KO	Cancer cell line	Female
CVCL_LB41	PathHunter U2OS TORC2 Nuclear Translocation	Cancer cell line	Female

Clinical trials (associated diseases)

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