ALKAL2

Summary

ALKAL2 (ALK and LTK ligand 2, HGNC:27683) is a protein-coding gene on chromosome 2p25.3, encoding ALK and LTK ligand 2 (Q6UX46). Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation.

Enables protein tyrosine kinase activator activity and signaling receptor binding activity. Involved in cell surface receptor protein tyrosine kinase signaling pathway; positive regulation of MAPK cascade; and positive regulation of neuron projection development. Is active in extracellular space.

Source: NCBI Gene 285016 — RefSeq curated summary.

At a glance

• GWAS associations: 26
• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_001002919

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27683
Approved symbol	ALKAL2
Name	ALK and LTK ligand 2
Location	2p25.3
Locus type	gene with protein product
Status	Approved
Aliases	AUGA
Ensembl gene	ENSG00000189292
Ensembl biotype	protein_coding
OMIM	619671
Entrez	285016

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 17 protein_coding, 1 retained_intron

ENST00000344414, ENST00000401489, ENST00000401503, ENST00000403610, ENST00000405290, ENST00000452023, ENST00000463919, ENST00000896929, ENST00000896930, ENST00000896931, ENST00000896932, ENST00000896933, ENST00000896934, ENST00000896935, ENST00000896936, ENST00000955429, ENST00000955430, ENST00000955431

RefSeq mRNA: 1 — MANE Select: NM_001002919 NM_001002919

CCDS: CCDS46218

Canonical transcript exons

ENST00000403610 — 6 exons

Exon	Start	End
ENSE00001377245	286123	286203
ENSE00001556616	279558	280152
ENSE00001897894	288013	288091
ENSE00002259337	287583	287892
ENSE00003598600	286290	286343
ENSE00003785964	283111	283175

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 98.57.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9726 / max 164.0091, expressed in 307 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26631	0.3567	90
26628	0.2399	122
26630	0.2064	85
26632	0.0732	26
26629	0.0714	31
26627	0.0162	3
26626	0.0056	3
26625	0.0033	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland cortex	UBERON:0035825	98.57	gold quality
adrenal cortex	UBERON:0001235	98.51	gold quality
right adrenal gland cortex	UBERON:0035827	98.49	gold quality
left adrenal gland	UBERON:0001234	98.47	gold quality
right adrenal gland	UBERON:0001233	98.38	gold quality
adrenal gland	UBERON:0002369	97.42	gold quality
body of pancreas	UBERON:0001150	96.97	gold quality
right ovary	UBERON:0002118	96.16	gold quality
left ovary	UBERON:0002119	95.63	gold quality
tibial artery	UBERON:0007610	92.99	gold quality
popliteal artery	UBERON:0002250	92.98	gold quality
left testis	UBERON:0004533	92.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.13	gold quality
right testis	UBERON:0004534	92.05	gold quality
ovary	UBERON:0000992	91.80	gold quality
pancreas	UBERON:0001264	91.41	gold quality
left uterine tube	UBERON:0001303	91.14	gold quality
decidua	UBERON:0002450	91.11	gold quality
testis	UBERON:0000473	91.05	gold quality
tibial nerve	UBERON:0001323	90.42	gold quality
upper lobe of left lung	UBERON:0008952	90.29	gold quality
right lung	UBERON:0002167	90.05	gold quality
body of uterus	UBERON:0009853	89.72	gold quality
adrenal tissue	UBERON:0018303	89.45	gold quality
upper lobe of lung	UBERON:0008948	89.39	gold quality
aorta	UBERON:0000947	88.92	gold quality
calcaneal tendon	UBERON:0003701	87.56	gold quality
lower lobe of lung	UBERON:0008949	86.70	gold quality
descending thoracic aorta	UBERON:0002345	86.36	gold quality
lung	UBERON:0002048	86.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	58.74
E-ANND-3	yes	9.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting ALKAL2, 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-3120-5P	100.00	65.56	965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 6)

• Only two related secreted factors, FAM150A and FAM150B (family with sequence similarity 150 member A and member B), stimulated LTK phosphorylation. (PMID:25331893)
• In conclusion, these data show that ALK is robustly activated by the FAM150A/B ligands. (PMID:26418745)
• Data show FAM150B, which was named as augmentor-alpha (AUG-alpha), binds and activtes both anaplastic lymphoma kinase (ALK) and tyrosine kinase (LTK). (PMID:26630010)
• activation of ALK/LTK family receptors by small ALKAL proteins (FAM150, AUG) conserved in vertebrates (PMID:29317532)
• ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. (PMID:33411331)
• The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer. (PMID:35351152)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	alkal2b	ENSDARG00000042815
danio_rerio	alkal2a	ENSDARG00000091073
mus_musculus	Alkal2	ENSMUSG00000054204
rattus_norvegicus	Alkal2	ENSRNOG00000005154

Protein

Protein identifiers

ALK and LTK ligand 2 — Q6UX46 (reviewed: Q6UX46)

Alternative names: Augmentor alpha

All UniProt accessions (5): A0A0B4J1W8, B5MC33, B5MCG6, H0Y3U4, Q6UX46

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation. Cytokine-binding is sufficient to activate LTK. In contrast, ALKAL2-driven activation of ALK is coupled with heparin-binding to ALK. Stimulation of ALK signaling is involved in neural development and regulation of energy expenditure.

Subunit / interactions. Homodimer; interchain disulfide bond is not required for homodimerization.

Subcellular location. Secreted. Cell membrane.

Tissue specificity. Widely expressed with highest levels in adrenal gland and modest levels in pancreas, testis and uterus.

Similarity. Belongs to the ALKAL family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UX46-1	1	yes
Q6UX46-2	2

RefSeq proteins (1): NP_001002919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029364	ALKL1/2	Family

Pfam: PF15129

UniProt features (21 total): helix 7, mutagenesis site 6, disulfide bond 3, splice variant 2, signal peptide 1, chain 1, strand 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7N00	ELECTRON MICROSCOPY	2.27
7LS0	X-RAY DIFFRACTION	3.05
9G5I	ELECTRON MICROSCOPY	3.2
7NWZ	X-RAY DIFFRACTION	4.17
7MZX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX46-F1	71.41	0.26

Functional residue map

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

Disulfide bonds (3): 66, 111–147, 125–134

Mutagenesis-validated functional residues (6):

Position	Phenotype
100	slightly reduced affinity for receptor tyrosine kinase ltk.
123	reduced affinity for receptor tyrosine kinases alk and ltk.
136	reduced affinity for receptor tyrosine kinases alk and ltk.
66	abolished interchain disulfide bond without affecting homodimerization.
94–100	abolished association with the cell membrane, leading to impaired activation of receptor tyrosine kinase alk.
97	slightly reduced affinity for receptor tyrosine kinase ltk.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-201556	Signaling by ALK
R-HSA-9842663	Signaling by LTK
R-HSA-162582	Signal Transduction
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 84 (showing top): chr2p25, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_RESPONSE_TO_FOOD, GOBP_NEUROGENESIS, GOMF_KINASE_ACTIVATOR_ACTIVITY, GTGCCTT_MIR506, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_MULTICELLULAR_ORGANISM_GROWTH, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_NEURON_PROJECTION_DEVELOPMENT, GOMF_CYTOKINE_ACTIVITY, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_ENERGY_HOMEOSTASIS, GOBP_CONNECTIVE_TISSUE_DEVELOPMENT

GO Biological Process (5): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of neuron projection development (GO:0010976), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of ERK5 cascade (GO:0070378), signal transduction (GO:0007165)

GO Molecular Function (5): cytokine activity (GO:0005125), receptor signaling protein tyrosine kinase activator activity (GO:0030298), receptor tyrosine kinase binding (GO:0030971), protein binding (GO:0005515), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of MAPK cascade	2
protein tyrosine kinase activator activity	2
cellular anatomical structure	2
enzyme-linked receptor protein signaling pathway	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
ERK5 cascade	1
regulation of ERK5 cascade	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
signaling receptor binding	1
protein tyrosine kinase binding	1
binding	1
transmembrane receptor protein tyrosine kinase activity	1
signaling receptor activator activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALKAL2	LTK	P29376	864
ALKAL2	SH3YL1	Q96HL8	605
ALKAL2	ALK	Q9UM73	593
ALKAL2	FAM110C	Q1W6H9	541
ALKAL2	ROS1	P08922	505
ALKAL2	DIS3L	Q8TF46	484
ALKAL2	ERGIC1	Q969X5	444
ALKAL2	MYCN	P04198	423
ALKAL2	PKIA	P04541	418
ALKAL2	TMEM18	Q96B42	396
ALKAL2	PLXNA2	O75051	395
ALKAL2	CTNND2	Q9UQB3	388
ALKAL2	SULF1	Q8IWU6	387
ALKAL2	PTN	P21246	380
ALKAL2	HSD11B1	P28845	380

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ALK	ALKAL2	psi-mi:“MI:0915”(physical association)	0.560
ALK	ALKAL2	psi-mi:“MI:0403”(colocalization)	0.560
ALKAL2	LTK	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): POTEE (Affinity Capture-MS), LRP2 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), LTK (Affinity Capture-MS), GPR98 (Affinity Capture-MS), PON2 (Affinity Capture-MS), CD109 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), CACNA2D1 (Affinity Capture-MS)

ESM2 similar proteins: B2RZ42, D4A6L0, E1BBQ2, J3QPP8, O02695, O62827, P01346, P01356, P06307, P06881, P09535, P12755, P12843, P15473, P16611, P17936, P20959, P22444, P22692, P24854, P47878, P49002, P49192, P49705, P53366, P55107, P55108, P56388, P80560, P97737, Q05716, Q08DX6, Q16568, Q26492, Q4RU86, Q58CS8, Q5T848, Q63475, Q68RJ9, Q6DVA0

Diamond homologs: B2RZ42, E7F5F0, E7FAP8, F8W2C9, J3QPP8, Q4RU86, Q6UX46, Q6UXT8, Q80UG6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1133 predictions. Top by Δscore:

Variant	Effect	Δscore
2:286285:CTTA:C	donor_loss	1.0000
2:286288:A:AC	donor_gain	1.0000
2:286289:C:CA	donor_loss	1.0000
2:286289:C:CC	donor_gain	1.0000
2:286339:AATTT:A	acceptor_gain	1.0000
2:286340:ATTT:A	acceptor_gain	1.0000
2:286341:TTT:T	acceptor_gain	1.0000
2:286342:TT:T	acceptor_gain	1.0000
2:286344:C:CC	acceptor_gain	1.0000
2:286344:CT:C	acceptor_loss	1.0000
2:286350:C:CT	acceptor_gain	1.0000
2:286351:A:T	acceptor_gain	1.0000
2:280148:CACTG:C	acceptor_gain	0.9900
2:280150:CTG:C	acceptor_gain	0.9900
2:285277:T:TA	donor_gain	0.9900
2:286121:A:AC	donor_gain	0.9900
2:286122:C:CC	donor_gain	0.9900
2:286122:CATG:C	donor_gain	0.9900
2:286288:AC:A	donor_gain	0.9900
2:286289:CC:C	donor_gain	0.9900
2:286347:T:TC	acceptor_gain	0.9900
2:287276:T:TA	donor_gain	0.9900
2:287578:CTCA:C	donor_loss	0.9900
2:287579:TCAC:T	donor_loss	0.9900
2:287580:CAC:C	donor_loss	0.9900
2:287581:AC:A	donor_gain	0.9900
2:287582:C:CT	donor_loss	0.9900
2:287582:CC:C	donor_gain	0.9900
2:287582:CCCA:C	donor_gain	0.9900
2:288162:A:C	donor_gain	0.9900

AlphaMissense

957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:286315:C:A	K94N	1.000
2:286315:C:G	K94N	1.000
2:283151:A:G	L138P	0.999
2:283151:A:T	L138H	0.999
2:283160:G:T	A135D	0.999
2:283162:G:C	C134W	0.999
2:283163:C:G	C134S	0.999
2:283163:C:T	C134Y	0.999
2:283164:A:G	C134R	0.999
2:283164:A:T	C134S	0.999
2:283168:T:A	K132N	0.999
2:283168:T:G	K132N	0.999
2:286136:G:C	C125W	0.999
2:286137:C:A	C125F	0.999
2:286137:C:G	C125S	0.999
2:286137:C:T	C125Y	0.999
2:286138:A:G	C125R	0.999
2:286138:A:T	C125S	0.999
2:286146:G:A	T122I	0.999
2:286156:A:C	Y119D	0.999
2:286179:C:G	C111S	0.999
2:286180:A:T	C111S	0.999
2:286307:A:C	F97C	0.999
2:286307:A:G	F97S	0.999
2:283142:A:G	L141P	0.998
2:283154:A:G	L137P	0.998
2:283163:C:A	C134F	0.998
2:283173:A:C	Y131D	0.998
2:286155:T:C	Y119C	0.998
2:286166:G:C	F115L	0.998

dbSNP variants (sampled 300 via entrez): RS1000235432 (2:286251 G>A), RS1000298119 (2:280852 G>A), RS1000327473 (2:281183 T>A), RS1000438974 (2:285082 TC>T), RS1000491307 (2:284638 A>G), RS1000614477 (2:281948 A>G), RS1000686552 (2:282175 G>C), RS1000823470 (2:283228 C>A,G,T), RS1000878425 (2:288710 A>C,G), RS1001297804 (2:279288 T>G), RS1001613115 (2:284181 A>G), RS1001768420 (2:289376 C>G,T), RS1002151181 (2:288205 G>A), RS1002218900 (2:289121 G>A), RS1002502143 (2:288393 C>T)

Disease associations

OMIM: gene MIM:619671 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST003542_30	Night sleep phenotypes	5.000000e-06
GCST003985_13	Breast size	3.000000e-08
GCST003993_21	Menarche (age at onset)	3.000000e-15
GCST004904_15	Body mass index	6.000000e-23
GCST004904_251	Body mass index	4.000000e-65
GCST005830_8	Hand grip strength	8.000000e-21
GCST005950_2	Body mass index x sex x age interaction (4df test)	5.000000e-75
GCST005951_193	Body mass index	1.000000e-72
GCST005952_2	Body mass index (age>50)	2.000000e-30
GCST005954_1	Body mass index x age interaction	4.000000e-07
GCST006291_61	Spherical equivalent or myopia (age of diagnosis)	2.000000e-10
GCST007240_7	Obese vs. thin	1.000000e-15
GCST008295_46	Number of decayed, missing and filled tooth surfaces or use of dentures	9.000000e-12
GCST008306_31	Dentures	1.000000e-10
GCST008526_53	Coffee consumption	5.000000e-09
GCST009107_6	Body mass index variance	1.000000e-11
GCST009108_2	Waist circumference variance	4.000000e-14
GCST009109_3	Hip circumference variance	2.000000e-09
GCST009121_4	Body mass index	4.000000e-51
GCST009122_2	Waist circumference	4.000000e-44
GCST009123_3	Hip circumference	6.000000e-45
GCST010002_382	Refractive error	6.000000e-25
GCST010988_275	Adult body size	7.000000e-60
GCST010989_192	Body size at age 10	4.000000e-134
GCST011703_42	Smoking initiation	6.000000e-13
GCST90002409_12	Childhood body mass index	3.000000e-07

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004340	body mass index
EFO:0006941	grip strength measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004847	age at onset
EFO:0007041	obese body mass index status
EFO:0010078	dentures
EFO:0006781	coffee consumption measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005670	smoking initiation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	6
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	increases expression	3
methylmercuric chloride	increases expression	2
mercuric bromide	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression, increases expression	2
bisphenol A	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
Malathion	increases expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	increases expression	1
Permethrin	increases expression	1

Clinical trials (associated diseases)

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