AKAP13

Summary

AKAP13 (A-kinase anchoring protein 13, HGNC:371) is a protein-coding gene on chromosome 15q25.3, encoding A-kinase anchor protein 13 (Q12802). Scaffold protein that plays an important role in assembling signaling complexes downstream of several types of G protein-coupled receptors.

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta.

Source: NCBI Gene 11214 — RefSeq curated summary.

At a glance

• GWAS associations: 42
• Clinical variants (ClinVar): 563 total
• Druggable target: yes
• MANE Select transcript: NM_007200

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:371
Approved symbol	AKAP13
Name	A-kinase anchoring protein 13
Location	15q25.3
Locus type	gene with protein product
Status	Approved
Aliases	Ht31, BRX, AKAP-Lbc, c-lbc, PROTO-LB, HA-3, ARHGEF13
Ensembl gene	ENSG00000170776
Ensembl biotype	protein_coding
OMIM	604686
Entrez	11214

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 6 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000361243, ENST00000394510, ENST00000394518, ENST00000557852, ENST00000558009, ENST00000558092, ENST00000558166, ENST00000558644, ENST00000558811, ENST00000559278, ENST00000559362, ENST00000559391, ENST00000559486, ENST00000559820, ENST00000560185, ENST00000560256, ENST00000560302, ENST00000560340, ENST00000560482, ENST00000560571, ENST00000560579, ENST00000560676, ENST00000560957, ENST00000612418, ENST00000915939

RefSeq mRNA: 3 — MANE Select: NM_007200 NM_001270546, NM_006738, NM_007200

CCDS: CCDS32319, CCDS32320, CCDS73778

Canonical transcript exons

ENST00000394518 — 37 exons

Exon	Start	End
ENSE00001390831	85744628	85749355
ENSE00002455459	85533584	85533880
ENSE00002465425	85521428	85521575
ENSE00002467371	85543772	85543955
ENSE00002519641	85578930	85582107
ENSE00002566229	85380603	85380798
ENSE00002705517	85485710	85485753
ENSE00003476228	85726410	85726486
ENSE00003480492	85723072	85723320
ENSE00003526751	85721991	85722116
ENSE00003527878	85710579	85710645
ENSE00003547171	85715788	85715923
ENSE00003586262	85719076	85719326
ENSE00003587817	85736090	85736134
ENSE00003602097	85722230	85722347
ENSE00003654797	85708019	85708086
ENSE00003665407	85585702	85585823
ENSE00003677208	85682158	85682212
ENSE00003712390	85743492	85743825
ENSE00003715833	85684741	85684873
ENSE00003717760	85735560	85735630
ENSE00003719307	85575131	85575329
ENSE00003729033	85730513	85730707
ENSE00003729494	85727066	85727247
ENSE00003732313	85645818	85645954
ENSE00003733237	85717290	85717402
ENSE00003734549	85718007	85718159
ENSE00003738105	85664563	85664755
ENSE00003739443	85734992	85735150
ENSE00003741213	85727381	85727463
ENSE00003742050	85669722	85669830
ENSE00003742457	85655417	85655787
ENSE00003743601	85740222	85740272
ENSE00003746524	85639374	85639449
ENSE00003747635	85658537	85658590
ENSE00003752615	85741046	85741495
ENSE00003784492	85693277	85693451

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.8987 / max 2130.0761, expressed in 1713 samples.

FANTOM5 promoters (44 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148173	16.2159	1744
148241	7.7548	718
148220	4.0729	568
148174	3.5415	1444
148232	2.7247	622
148187	1.9233	202
148219	1.5477	400
148199	1.5124	314
148186	1.4662	217
148204	1.1706	230

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.60	gold quality
tendon	UBERON:0000043	99.38	gold quality
calcaneal tendon	UBERON:0003701	99.33	gold quality
lower lobe of lung	UBERON:0008949	98.68	gold quality
sural nerve	UBERON:0015488	98.50	gold quality
colonic epithelium	UBERON:0000397	98.48	gold quality
visceral pleura	UBERON:0002401	98.25	gold quality
pylorus	UBERON:0001166	98.20	gold quality
apex of heart	UBERON:0002098	98.15	gold quality
cauda epididymis	UBERON:0004360	98.09	gold quality
heart right ventricle	UBERON:0002080	97.90	gold quality
vena cava	UBERON:0004087	97.52	gold quality
synovial joint	UBERON:0002217	97.50	gold quality
body of uterus	UBERON:0009853	97.44	gold quality
myometrium	UBERON:0001296	97.40	gold quality
cardia of stomach	UBERON:0001162	97.35	gold quality
right lung	UBERON:0002167	97.25	gold quality
sperm	CL:0000019	97.19	gold quality
pericardium	UBERON:0002407	97.18	gold quality
upper lobe of lung	UBERON:0008948	97.02	gold quality
nipple	UBERON:0002030	96.95	gold quality
upper lobe of left lung	UBERON:0008952	96.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.92	gold quality
cardiac ventricle	UBERON:0002082	96.90	gold quality
granulocyte	CL:0000094	96.89	gold quality
leukocyte	CL:0000738	96.89	gold quality
heart left ventricle	UBERON:0002084	96.86	gold quality
monocyte	CL:0000576	96.85	gold quality
mononuclear cell	CL:0000842	96.85	gold quality
decidua	UBERON:0002450	96.84	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	30.99
E-HCAD-25	yes	17.03
E-CURD-119	yes	13.40
E-CURD-122	yes	11.41
E-GEOD-130148	yes	9.19
E-GEOD-131882	no	1551.06
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

219 targeting AKAP13, 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-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-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593

Literature-anchored findings (GeneRIF, showing 38)

• Results show that alpha-catulin co-expression leads to increased Lbc-induced serum response factor activation and may modulate Rho pathway signaling in vivo by providing a scaffold for the Lbc Rho guanine nucleotide exchange factor. (PMID:12270917)
• The HA-3 peptide, VTEPGTAQY, is encoded by the lymphoid blast crisis oncogene, showing for the 1st time that a leukemia-associated oncogene can give rise to immunogenic T-cell epitopes that may participate in antihost & antileukemic alloimmune responses. (PMID:12663445)
• Proto-Lbc mutant expression led to decreased levels of Galpha12-induced RhoA activation in vivo. (PMID:14636890)
• results indicate that guanine nucleotide exchange factor Lbc is a novel signal transducer for RhoA-mediated NF-kappaB activation in human peripheral blood monocytes stimulated with bacterial products (PMID:14660653)
• Anchoring of both PKA and 14-3-3 inhibits the Rho-GEF activity of the AKAP-Lbc signaling complex. (PMID:15229649)
• Rho-GEF activity of AKAP-Lbc is mediated by leucine zipper-mediated homo-oligomerization regulates (PMID:15691829)
• significant association seen between rare AKAP13 Lys526Glyn variant and increased risk of development breast cancer; this variant might affect susceptibility to other cancers and might influence response to anticancer drugs targeting rho proteins (PMID:16234258)
• Yeast 2-Hybrid experiments identified a strong and novel interaction between the transglutaminase moiety and protein kinase A anchor protein 13 (AKAP13) (PMID:16301118)
• The spatiotemporal expression of Brx was altered in eutopic endometrium of women with endometriosis. (PMID:16412732)
• Brx modifies the actions of glucocorticoids, enhancing the transcriptional activity of glucocorticoid receptor (GR) by interacting with GR and by attracting Rho family G proteins to the GR-induced transcriptisome (PMID:16469733)
• AKAP13 plays a role in TLR2-mediated NF-kappaB activation; GEF-containing scaffold proteins may confer specificity to innate immune responses downstream of TLRs (PMID:17878165)
• findings show the BNIP2 & BCH domain of BNIPXL interacts with specific conformers of RhoA & mediates association with catalytic DH-PH domains of Lbc, a RhoA-specific guanine nucleotide exchange factor; BNIPXL inhibits Lbc-induced oncogenic transformation (PMID:18445682)
• Data suggest that LC3 binding maintains AKAP-Lbc in an inactive state that displays a reduced ability to promote downstream signaling. (PMID:19696020)
• The positive expression rate of AKAP13 protein in colorectal carcinoma (52.3%) was significantly higher than those in adenoma (9.1%) and normal tissue (34.7%) (P = 0.006) by immunohistochemical staining. (PMID:19779964)
• backbone and side chain (1)H, (13)C and (15)N resonance assignments of a 20 kDa construct comprising the uniformly (13)C and( 15)N labeled AKAP13-PH domain and an associated helix from the DH domain which is required for its stable expression (PMID:19888694)
• Data show that the RASGRP1/APTX gene expression ratio was higher in the responder while the AKAP13 expression was higher in the non-responders. (PMID:19960345)
• the Lbc/alpha-catulin axis participates in 5-HT-induced PASMC mitogenesis and RhoA/ROCK signaling, and may be an interventional target in diseases involving vascular smooth muscle remodeling. (PMID:20696764)
• third new locus (rs6496932), on 15q25.3 (beta = 0.13, P = 1.4 x 10(-8)), was within a wide linkage disequilibrium block extending into the 5’ end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface (PMID:20719862)
• Study demonstrates that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras (KSR-1) form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2. (PMID:21102438)
• A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling complex involved in alpha1-adrenergic receptor-induced p38 activation. (PMID:21224381)
• One SNP (rs11638762), in the GATA-3 binding site upstream of the AKAP13 gene, was significantly replicated in another cohort for systolic blood pressure (PMID:21228793)
• Amplification of AKAP-13 is associated with metastatic and aggressive papillary thyroid carcinomas. (PMID:22161024)
• Thus AKAP-Lbc may serve an ancillary cardioprotective role by favouring the association of PKA with Hsp20. (PMID:22731613)
• Shp2 is a component of the AKAP-Lbc complex and is inhibited by protein kinase A under pathological hypertrophic conditions in the heart. (PMID:23045525)
• activation of IKKbeta within the AKAP-Lbc complex promotes NF-kappaB-dependent production of interleukin-6 (PMID:23090968)
• pleckstrin homology (PH) domain of Lbc is located at the C-terminal end of the protein and is shown here to specifically recognize activated RhoA rather than lipids (PMID:24993829)
• Isothermal titration calorimetry showed that AKAP-Lbc has only micromolar affinity for RhoA, which combined with the presence of potential binding pockets for small molecules on AKAP-Lbc, raises the possibility of targeting AKAP-Lbc with GEF inhibitors. (PMID:25186459)
• Studied molecular interactions involving anchoring protein AKAP13 in the process of PKA-induced tamoxifen resistance in breast cancer specimens and cell lines. (PMID:26272591)
• evaluation of MAGT1 and AKAP13 expression in clinical hepatocellular carcinoma tissues by immunohistochemistry suggested that both proteins were strongly expressed in tumor tissues with significantly higher average immunoreactive scores of Remmele and Stegner (IRS) than in non-tumor tissues (PMID:26617690)
• AKAP-Lbc emerges as a coordinator of signals that protect cardiomyocytes against the toxic effects of DOX. (PMID:28923249)
• We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with Idiopathic pulmonary fibrosis, and AKAP13 mRNA expression was 1.42-times higher in lung tissue from patients with Idiopathic pulmonary fibrosis than that in lung tissue from controls. (PMID:29066090)
• Study of fibroid samples from patients and immortalized uterine fibroid cell lines and COS-7 cells suggest an intersection of mechanical signaling and progesterone receptor signaling involving AKAP13 through ERK. (PMID:30239831)
• Identification of novel splicing patterns and differential gene expression in RE+/FECD- samples provides new insights and more relevant gene targets that may be protective against FECD disease in vulnerable patients with TCF4 CTG TNR expansions. (PMID:31469403)
• Prognostic value of AKAP13 methylation and expression in lung squamous cell carcinoma. (PMID:32208871)
• CD47 promotes T-cell lymphoma metastasis by up-regulating AKAP13-mediated RhoA activation. (PMID:33406263)
• AKAP13 couples GPCR signaling to mTORC1 inhibition. (PMID:34673774)
• The role of Hippo pathway signaling and A-kinase anchoring protein 13 in primordial follicle activation and inhibition. (PMID:35560009)
• AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells. (PMID:36401072)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef28b	ENSDARG00000091607
mus_musculus	Akap13	ENSMUSG00000066406
rattus_norvegicus	Akap13	ENSRNOG00000010964

Protein

Protein identifiers

A-kinase anchor protein 13 — Q12802 (reviewed: Q12802)

Alternative names: AKAP-Lbc, Breast cancer nuclear receptor-binding auxiliary protein, Guanine nucleotide exchange factor Lbc, Human thyroid-anchoring protein 31, Lymphoid blast crisis oncogene, Non-oncogenic Rho GTPase-specific GTP exchange factor, Protein kinase A-anchoring protein 13, p47

All UniProt accessions (12): Q12802, A0A087WTD7, A0A087WX73, A0A087WY36, A0A087WYS7, A0A087X047, A8MYJ1, H0YK18, H0YK84, H0YLH1, H0YMI5, H0YMW2

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein that plays an important role in assembling signaling complexes downstream of several types of G protein-coupled receptors. Activates RHOA in response to signaling via G protein-coupled receptors via its function as Rho guanine nucleotide exchange factor. May also activate other Rho family members. Part of a kinase signaling complex that links ADRA1A and ADRA1B adrenergic receptor signaling to the activation of downstream p38 MAP kinases, such as MAPK11 and MAPK14. Part of a signaling complex that links ADRA1B signaling to the activation of RHOA and IKBKB/IKKB, leading to increased NF-kappa-B transcriptional activity. Part of a RHOA-dependent signaling cascade that mediates responses to lysophosphatidic acid (LPA), a signaling molecule that activates G-protein coupled receptors and potentiates transcriptional activation of the glucocorticoid receptor NR3C1. Part of a signaling cascade that stimulates MEF2C-dependent gene expression in response to lysophosphatidic acid (LPA). Part of a signaling pathway that activates MAPK11 and/or MAPK14 and leads to increased transcription activation of the estrogen receptors ESR1 and ESR2. Part of a signaling cascade that links cAMP and EGFR signaling to BRAF signaling and to PKA-mediated phosphorylation of KSR1, leading to the activation of downstream MAP kinases, such as MAPK1 or MAPK3. Functions as a scaffold protein that anchors cAMP-dependent protein kinase (PKA) and PRKD1. This promotes activation of PRKD1, leading to increased phosphorylation of HDAC5 and ultimately cardiomyocyte hypertrophy. Has no guanine nucleotide exchange activity on CDC42, Ras or Rac. Required for normal embryonic heart development, and in particular for normal sarcomere formation in the developing cardiomyocytes. Plays a role in cardiomyocyte growth and cardiac hypertrophy in response to activation of the beta-adrenergic receptor by phenylephrine or isoproterenol. Required for normal adaptive cardiac hypertrophy in response to pressure overload. Plays a role in osteogenesis.

Subunit / interactions. Interacts with the cAMP-dependent protein kinase (PKA) holoenzyme and with the regulatory subunit PRKAR2A. Interacts with RHOA. Also interacts with RHOB and RHOC. Identified in a ternary complex with RHOA and PRKAR2A. Identified in a complex with NR3C1 and RHOA. Interacts with BRAF and KSR1. Identified in a complex with BRAF and KSR1. Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK. Interacts (phosphorylated form) with YWHAB and YWHAZ. Interaction with YWHAB inhibits activation of RHOA, interferes with PKN1 binding and activation of MAP kinases. Interacts with GNA12. Interacts with IKBKB. Interacts with ESR1, THRA, PPARA and NME2. Interacts (via the C-terminal domain after the PH domain) with MEF2C and RXRB. Interacts (via the C-terminal domain after the PH domain) with PRKD1.

Subcellular location. Cytoplasm. Cytosol. Cell cortex. Nucleus. Membrane.

Tissue specificity. Detected in mammary gland. Detected in heart (at protein level). Expressed as a 5.3 kb transcript in hematopoietic cells, skeletal muscle, lung, heart, estrogen-responsive reproductive tissues, including breast ductal epithelium. Also found in testis and breast cancer cell lines. Predominantly expressed as a 10 kb transcript in the heart and at lower levels in the lung, placenta, kidney, pancreas, skeletal muscle and liver. Transcripts of between 6-9 kb are also expressed in myeloid and lymphoid lineages, a variety of epithelial tissues, and in skeletal muscle.

Domain organisation. The DH domain is sufficient for interaction with RHOA, and for guanine nucleotide exchange (GEF) activity with RHOA. Forms that lack C-terminal regulatory domains have transforming activity and function as oncogenes. The PH domain does not play a role in lipid-binding. Instead, it inhibits the guanine nucleotide exchange (GEF) activity of the isolated DH domain (in vitro). The C-terminal domain after the PH domain is involved in protein-protein interactions that are required for normal, compensatory cardiac hypertrophy in response to pressure overload.

Isoforms (4)

UniProt ID	Names	Canonical?
Q12802-1	1	yes
Q12802-2	2
Q12802-4	3
Q12802-5	4

RefSeq proteins (3): NP_001257475, NP_006729, NP_009131* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001849	PH_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR018459	RII-bd_1	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR041020	PH_16	Domain
IPR046349	C1-like_sf	Homologous_superfamily
IPR051632	Rho_GEF	Family

Pfam: PF00621, PF10522, PF17838

UniProt features (149 total): modified residue 28, helix 18, region of interest 16, compositionally biased region 16, sequence conflict 15, sequence variant 14, mutagenesis site 14, strand 13, splice variant 5, turn 3, coiled-coil region 3, domain 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6BCA	X-RAY DIFFRACTION	2
4D0N	X-RAY DIFFRACTION	2.1
4D0O	X-RAY DIFFRACTION	2.75
2DRN	SOLUTION NMR
2LG1	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q12802 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Post-translational modifications (28): 790, 815, 953, 983, 1489, 1507, 1540, 1565, 1602, 1642, 1645, 1647, 1670, 1876, 1895, 1929, 1930, 1932, 1945, 2345 …

Mutagenesis-validated functional residues (14):

Position	Phenotype
1251	abolishes interaction with prkar2a and leads to constitutive activation of rhoa; when associated with p-1260.
1260	abolishes interaction with prkar2aand leads to constitutive activation of rhoa; when associated with p-1251.
1265	abolishes interaction with prkar2a.
1565	abolishes interaction with ywhab, leading to constitutive activation of rhoa and mapk14.
2001	decreases guanyl nucleotide exchange activity toward rhoa.
2136	decreases guanyl nucleotide exchange activity toward rhoa.
2148	abolishes guanyl nucleotide exchange activity toward rhoa.
2152	abolishes guanyl nucleotide exchange activity toward rhoa.
2153	loss of guanyl nucleotide exchange activity toward rhoa.
2189	reduces guanyl nucleotide exchange activity toward rhoa.
2189	abolishes guanyl nucleotide exchange activity toward rhoa.
2289	decreases guanyl nucleotide exchange activity toward rhoa.
2299	decreases guanyl nucleotide exchange activity toward rhoa.
2324	impairs interaction with ikbkb.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 331 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_MUSCLE_TISSUE_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, TGCACTT_MIR519C_MIR519B_MIR519A, ATACCTC_MIR202, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOMF_GTPASE_BINDING, CAGGTCC_MIR492

GO Biological Process (12): G protein-coupled receptor signaling pathway (GO:0007186), heart development (GO:0007507), regulation of Rho protein signal transduction (GO:0035023), positive regulation of Rho protein signal transduction (GO:0035025), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), regulation of small GTPase mediated signal transduction (GO:0051056), cardiac muscle cell differentiation (GO:0055007), regulation of sarcomere organization (GO:0060297), bone development (GO:0060348), adrenergic receptor signaling pathway (GO:0071875), MAPK cascade (GO:0000165), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (8): MAP kinase scaffold activity (GO:0005078), guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), small GTPase binding (GO:0031267), protein kinase A binding (GO:0051018), molecular adaptor activity (GO:0060090), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), cytosol (GO:0005829), cell cortex (GO:0005938), membrane (GO:0016020), cytoplasm (GO:0005737), actin cytoskeleton (GO:0015629), cortical actin cytoskeleton (GO:0030864)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RHO GTPase cycle	3
Signal Transduction	3
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
animal organ development	2
Rho protein signal transduction	2
binding	2
cytoplasm	2
G protein-coupled receptor activity	1
signal transduction	1
circulatory system development	1
regulation of small GTPase mediated signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
cardiocyte differentiation	1
cardiac muscle tissue development	1
striated muscle cell differentiation	1
sarcomere organization	1
regulation of actomyosin structure organization	1
regulation of supramolecular fiber organization	1
skeletal system development	1
adrenergic receptor activity	1
G protein-coupled receptor signaling pathway	1
intracellular signaling cassette	1
regulation of signal transduction	1
intracellular signal transduction	1
MAPK cascade	1
signaling adaptor activity	1
mitogen-activated protein kinase binding	1
protein complex scaffold activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
transition metal ion binding	1
GTPase binding	1
protein binding	1
molecular_function	1
cation binding	1

Protein interactions and networks

STRING

1700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKAP13	RHOA	P06749	991
AKAP13	AKAP1	Q92667	921
AKAP13	CTNNAL1	Q9UBT7	817
AKAP13	PRKD1	Q15139	806
AKAP13	MCF2	P10911	784
AKAP13	PRKACA	P17612	782
AKAP13	PRKACB	P22694	776
AKAP13	PRKD3	O94806	773
AKAP13	AKAP12	Q02952	768
AKAP13	PRKD2	Q9BZL6	766
AKAP13	AKAP9	Q99996	711
AKAP13	AKAP5	P24588	700
AKAP13	AKAP7	O43687	699
AKAP13	PRKACG	P22612	699
AKAP13	KSR1	Q8IVT5	699

IntAct

93 interactions, top by confidence:

A	B	Type	Score
AKAP13	YWHAB	psi-mi:“MI:0915”(physical association)	0.890
AKAP13	YWHAB	psi-mi:“MI:0914”(association)	0.890
AKAP13	YWHAG	psi-mi:“MI:0915”(physical association)	0.880
YWHAZ	AKAP13	psi-mi:“MI:0915”(physical association)	0.790
	PRKAR1A	psi-mi:“MI:0914”(association)	0.700
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
AKAP13	ESR1	psi-mi:“MI:0407”(direct interaction)	0.590
AKAP13	ESR1	psi-mi:“MI:0915”(physical association)	0.590
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
AKAP13	TGM2	psi-mi:“MI:0915”(physical association)	0.540
TGM2	AKAP13	psi-mi:“MI:0403”(colocalization)	0.540
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PRKAR2B	AMY1A	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
AKAP13	THRA	psi-mi:“MI:0407”(direct interaction)	0.440
Ppara	AKAP13	psi-mi:“MI:0407”(direct interaction)	0.440
AKAP13	MKI67	psi-mi:“MI:0915”(physical association)	0.400
AKAP13	ARHGEF18	psi-mi:“MI:0915”(physical association)	0.400
ARHGEF18	AKAP13	psi-mi:“MI:0915”(physical association)	0.400
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (147): MAP1LC3A (Two-hybrid), MAP1LC3A (Reconstituted Complex), MAP1LC3A (Affinity Capture-Western), AKAP13 (Reconstituted Complex), AKAP13 (Reconstituted Complex), RHOA (Affinity Capture-Western), AKAP13 (Far Western), YWHAG (Reconstituted Complex), YWHAG (Affinity Capture-Western), AKAP13 (Affinity Capture-MS), UBB (Affinity Capture-MS), MTR (Affinity Capture-MS), AKAP13 (Affinity Capture-MS), PRKD1 (Reconstituted Complex), PRKAR2A (Reconstituted Complex)

ESM2 similar proteins: A2ADZ8, A6NNH2, D2J0Y4, D3YU32, P0C2Y1, Q0VET5, Q12802, Q14676, Q149B8, Q283Q6, Q2TBI7, Q3KR64, Q3U0P1, Q4KMZ1, Q4R736, Q5QJ38, Q5R5G4, Q5T1N1, Q5TM68, Q5VWK0, Q5VYM1, Q5ZK13, Q68A65, Q6AZ54, Q6NXZ1, Q6PG16, Q6PIX9, Q7YR40, Q7Z572, Q86Y26, Q8BHP2, Q8BHW6, Q8C0D9, Q8C5V8, Q8C9M2, Q8CGM2, Q8N5Q1, Q8NCD3, Q8WP21, Q924C5

Diamond homologs: B2DCZ9, E9Q394, F1M3G7, P0C6P5, P97433, Q12802, Q5FVC2, Q60875, Q6P9R4, Q6ZSZ5, Q865S3, Q8N1W1, Q92974, Q9NZN5, Q61210, Q92888, Q9Z1I6, Q8R4H2, O15085, O94827, Q5R6F2, Q5ZLX4, Q66T02, Q6RFZ7, Q9ES67, Q9N0A8, Q9NR81

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKACA	down-regulates	AKAP13	phosphorylation
PRKACA	up-regulates	AKAP13	phosphorylation
AKAP13	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
GNA12	“up-regulates activity”	AKAP13	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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	115.9×	2e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	102.2×	3e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	102.2×	3e-11
Activation of BH3-only proteins	7	75.6×	2e-10
RHO GTPases activate PKNs	8	55.2×	1e-10
Intrinsic Pathway for Apoptosis	8	50.9×	2e-10
FOXO-mediated transcription	5	36.5×	6e-06
Apoptosis	8	29.2×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	32.7×	1e-04
intracellular protein localization	10	18.7×	7e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	449
Likely benign	47
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

8635 predictions. Top by Δscore:

Variant	Effect	Δscore
15:85380831:G:T	donor_gain	1.0000
15:85485754:G:GG	donor_gain	1.0000
15:85519578:GC:G	donor_gain	1.0000
15:85519579:C:G	donor_gain	1.0000
15:85521424:CTA:C	acceptor_loss	1.0000
15:85521425:TA:T	acceptor_loss	1.0000
15:85521426:A:AG	acceptor_gain	1.0000
15:85521426:AG:A	acceptor_gain	1.0000
15:85521426:AGGGT:A	acceptor_gain	1.0000
15:85521427:G:GC	acceptor_loss	1.0000
15:85521427:G:GG	acceptor_gain	1.0000
15:85521427:GG:G	acceptor_gain	1.0000
15:85521427:GGGT:G	acceptor_gain	1.0000
15:85521427:GGGTG:G	acceptor_gain	1.0000
15:85521572:CCTG:C	donor_gain	1.0000
15:85521574:TGGTA:T	donor_loss	1.0000
15:85521576:G:GC	donor_loss	1.0000
15:85521576:G:GG	donor_gain	1.0000
15:85543764:A:AG	acceptor_gain	1.0000
15:85543765:T:G	acceptor_gain	1.0000
15:85543767:TACAG:T	acceptor_loss	1.0000
15:85543769:C:G	acceptor_gain	1.0000
15:85543770:A:AC	acceptor_loss	1.0000
15:85543770:A:AG	acceptor_gain	1.0000
15:85543770:AGAT:A	acceptor_gain	1.0000
15:85543771:G:A	acceptor_loss	1.0000
15:85543771:G:GC	acceptor_gain	1.0000
15:85543771:GA:G	acceptor_gain	1.0000
15:85543771:GAT:G	acceptor_gain	1.0000
15:85543771:GATG:G	acceptor_gain	1.0000

AlphaMissense

18563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:85693400:T:C	C1805R	0.999
15:85719112:T:C	L2013P	0.999
15:85722285:T:C	L2145P	0.999
15:85722297:G:C	R2149P	0.999
15:85727100:T:C	L2286P	0.999
15:85727109:G:T	R2289I	0.999
15:85727110:A:C	R2289S	0.999
15:85727110:A:T	R2289S	0.999
15:85727138:T:C	F2299L	0.999
15:85727140:C:A	F2299L	0.999
15:85727140:C:G	F2299L	0.999
15:85727142:T:C	L2300P	0.999
15:85727205:G:C	R2321P	0.999
15:85727213:T:A	W2324R	0.999
15:85727213:T:C	W2324R	0.999
15:85533847:T:A	W149R	0.998
15:85533847:T:C	W149R	0.998
15:85655738:T:A	W1566R	0.998
15:85655738:T:C	W1566R	0.998
15:85693445:T:C	C1820R	0.998
15:85708034:T:A	V1827D	0.998
15:85708045:T:C	C1831R	0.998
15:85718084:T:A	W1976R	0.998
15:85718084:T:C	W1976R	0.998
15:85719112:T:A	L2013H	0.998
15:85722036:T:C	F2100L	0.998
15:85722038:T:A	F2100L	0.998
15:85722038:T:G	F2100L	0.998
15:85722306:A:T	K2152M	0.998
15:85722307:G:C	K2152N	0.998

dbSNP variants (sampled 300 via entrez): RS1000017603 (15:85510434 G>A), RS1000048401 (15:85734423 A>G), RS1000055743 (15:85487233 A>G), RS1000059003 (15:85467899 C>G,T), RS1000062013 (15:85619458 G>A), RS1000069641 (15:85423621 G>A), RS1000072616 (15:85594439 G>A), RS1000076073 (15:85473932 G>A), RS1000085849 (15:85740389 C>T), RS1000100916 (15:85703167 A>G), RS1000106612 (15:85741947 A>C), RS1000115228 (15:85668584 C>G), RS1000128772 (15:85690049 G>A,C), RS1000137610 (15:85638198 T>A), RS1000145374 (15:85555714 G>A)

Disease associations

OMIM: gene MIM:604686 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST000775_1	Central corneal thickness	1.000000e-08
GCST001204_10	Response to platinum-based chemotherapy (carboplatin)	9.000000e-06
GCST001806_22	Corneal structure	7.000000e-13
GCST002889_6	Psoriasis	2.000000e-06
GCST004602_215	Mean corpuscular volume	8.000000e-09
GCST004608_202	Granulocyte percentage of myeloid white cells	4.000000e-09
GCST004609_219	Monocyte percentage of white cells	7.000000e-10
GCST004986_6	Idiopathic pulmonary fibrosis	1.000000e-09
GCST005196_12	Coronary artery disease	6.000000e-07
GCST005580_181	Intraocular pressure	2.000000e-08
GCST005580_293	Intraocular pressure	2.000000e-09
GCST005667_14	Central corneal thickness	2.000000e-15
GCST007267_8	Systolic blood pressure	5.000000e-13
GCST007269_151	Pulse pressure	4.000000e-10
GCST007928_14	Medication use (diuretics)	4.000000e-10
GCST008362_57	Birth weight	1.000000e-08
GCST008362_80	Birth weight	2.000000e-06
GCST008363_101	Offspring birth weight	3.000000e-18
GCST008363_124	Offspring birth weight	8.000000e-12
GCST009391_1277	Metabolite levels	4.000000e-06
GCST009414_23	Central corneal thickness	3.000000e-13
GCST009597_194	Multiple sclerosis	8.000000e-07
GCST009758_12	Idiopathic pulmonary fibrosis	1.000000e-10
GCST010002_103	Refractive error	5.000000e-08
GCST010994_9	High myopia	3.000000e-10
GCST011801_17	Post-bronchodilator lung function in asthma (FEV1/FVC)	9.000000e-08
GCST012226_105	Waist circumference adjusted for body mass index	5.000000e-12
GCST012231_135	A body shape index	2.000000e-08
GCST90000654_62	Central corneal thickness	2.000000e-29
GCST90002384_348	Hemoglobin	1.000000e-10

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0004345	corneal topography
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0009928	Diuretic use measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0010546	uridine measurement
EFO:0004713	FEV/FVC ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0005091	monocyte count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523643 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, affects cotreatment, increases expression, decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
Progesterone	affects cotreatment, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	increases expression	1
tetrabromobisphenol A	decreases expression	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
versicolorin A	decreases expression	1
coumarin	affects phosphorylation	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419743	Binding	Inhibition of FLAG-tagged human LBC RhoGEF DH-PH module expressed in mouse NIH/3T3 cells assessed as reduction in human full length RhoA (1 to 193 residues) interaction with LBC RhoGEF at 10 to 50 uM incubated for 1 hr by Western blot analy	Small-molecule inhibitors targeting g-protein-coupled rho guanine nucleotide exchange factors

Clinical trials (associated diseases)

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