APLP2

Summary

APLP2 (amyloid beta precursor like protein 2, HGNC:598) is a protein-coding gene on chromosome 11q24.3, encoding Amyloid beta precursor like protein 2 (Q06481). May play a role in the regulation of hemostasis.

This gene encodes amyloid precursor- like protein 2 (APLP2), which is a member of the APP (amyloid precursor protein) family including APP, APLP1 and APLP2. This protein is ubiquitously expressed. It contains heparin-, copper- and zinc- binding domains at the N-terminus, BPTI/Kunitz inhibitor and E2 domains in the middle region, and transmembrane and intracellular domains at the C-terminus. This protein interacts with major histocompatibility complex (MHC) class I molecules. The synergy of this protein and the APP is required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. This protein has been implicated in the pathogenesis of Alzheimer’s disease. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 334 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 159 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 38 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.72 (unconstrained)
• MANE Select transcript: NM_001142276
• Notable: 159 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:598
Approved symbol	APLP2
Name	amyloid beta precursor like protein 2
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Aliases	APPH
Ensembl gene	ENSG00000084234
Ensembl biotype	protein_coding
OMIM	104776
Entrez	334

Gene structure

Transcript identifiers

Ensembl transcripts: 70 — 46 protein_coding, 9 protein_coding_CDS_not_defined, 8 nonsense_mediated_decay, 7 retained_intron

MANE Select: ENST00000338167

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 5, TSL 2: 6, TSL 3: 2, TSL 4: 8, TSL 5: 4

ENST00000338167, ENST00000263574, ENST00000278756, ENST00000345598, ENST00000461918, ENST00000525215, ENST00000525604, ENST00000526330, ENST00000527702, ENST00000528499, ENST00000529235, ENST00000529483, ENST00000529701, ENST00000530132, ENST00000530493, ENST00000532456, ENST00000533195, ENST00000533532, ENST00000533616, ENST00000533618, ENST00000533713, ENST00000533860, ENST00000534001, ENST00000534582, ENST00000534761, ENST00000650012, ENST00000881671, ENST00000881672, ENST00000881673, ENST00000881674, ENST00000881675, ENST00000881676, ENST00000881677, ENST00000881678, ENST00000881679, ENST00000881680, ENST00000881681, ENST00000881682, ENST00000881683, ENST00000881684, ENST00000881685, ENST00000881686, ENST00000881687, ENST00000881688, ENST00000881689, ENST00000881690, ENST00000917763, ENST00000917764, ENST00000917765, ENST00000917766, ENST00000917767, ENST00000917768, ENST00000917769, ENST00000917770, ENST00000917771, ENST00000917772, ENST00000917773, ENST00000969908, ENST00000969909, ENST00000969910, ENST00000969911, ENST00001000342, ENST00001000344, ENST00001000345, ENST00001047062, ENST00001087875, ENST00001087876, ENST00001109995, ENST00001109996, ENST00001143446

RefSeq mRNA: 30 — MANE Select: NM_001142276 NM_001142276, NM_001142277, NM_001142278, NM_001243299, NM_001328682, NM_001328684, NM_001328685, NM_001328686, NM_001382526, NM_001382527, NM_001382528, NM_001382529, NM_001382530, NM_001382531, NM_001382532, NM_001382533, NM_001382534, NM_001382535, NM_001382536, NM_001382537, NM_001382538, NM_001382539, NM_001382540, NM_001382541, NM_001382542, NM_001382543, NM_001382544, NM_001382545, NM_001382546, NM_001642

CCDS: CCDS44773, CCDS44774, CCDS44775, CCDS58196, CCDS8486

Canonical transcript exons

ENST00000338167 — 17 exons

Exon	Start	End
ENSE00000541209	130123612	130123779
ENSE00002185583	130143347	130144805
ENSE00003499847	130129048	130129206
ENSE00003524562	130120706	130120818
ENSE00003527308	130141919	130142074
ENSE00003533331	130122305	130122513
ENSE00003541263	130127766	130127840
ENSE00003543423	130130038	130130166
ENSE00003581010	130109429	130109602
ENSE00003583200	130110538	130110661
ENSE00003602308	130133629	130133728
ENSE00003604190	130140398	130140483
ENSE00003627874	130135563	130135715
ENSE00003658624	130069894	130070082
ENSE00003664207	130126700	130126830
ENSE00003667345	130141498	130141572
ENSE00003692516	130121614	130121810

Expression profiles

Bgee: expression breadth ubiquitous, 306 present calls, max score 99.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 302.9552 / max 7723.6845, expressed in 1825 samples.

Highest expression (Bgee): renal medulla, choroid plexus epithelium, trigeminal ganglion, medial globus pallidus, monocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APLP2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 38 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 57 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	7.4e-47	+1.40	11:130123537:C:T
Cells Cultured fibroblasts	sqtl	3.7e-26	+1.01	11:130123529:C:G
Artery Tibial	sqtl	6.6e-25	-1.26	11:130123529:C:G
Skin Sun Exposed Lower leg	sqtl	3.0e-24	+0.91	11:130123537:C:T
Esophagus Muscularis	sqtl	5.1e-24	+1.30	11:130123537:C:T
Nerve Tibial	sqtl	2.0e-23	+0.98	11:130123529:C:G
Thyroid	sqtl	4.5e-22	+1.04	11:130123537:C:T
Muscle Skeletal	sqtl	1.3e-20	+0.71	11:130123537:C:T
Adipose Subcutaneous	sqtl	8.3e-18	+0.69	11:130123537:C:T
Muscle Skeletal	eqtl	6.2e-15	-0.44	11:130101603:C:T
Heart Atrial Appendage	sqtl	2.6e-14	+0.73	11:130123541:A:G
Artery Aorta	sqtl	2.6e-13	+1.49	11:130123529:C:G
Testis	sqtl	3.9e-13	+1.19	11:130123529:C:G
Skin Not Sun Exposed Suprapubic	sqtl	8.2e-12	+0.96	11:130123529:C:G
Adipose Visceral Omentum	sqtl	5.4e-11	+0.68	11:130123537:C:T
Brain Cerebellum	sqtl	4.8e-10	+1.35	11:130154541:A:G
Esophagus Gastroesophageal Junction	sqtl	8.6e-10	+0.77	11:130123541:A:G
Colon Sigmoid	sqtl	1.9e-09	+1.36	11:130123529:C:G
Brain Cortex	sqtl	3.1e-09	+0.94	11:130123529:C:G
Brain Cerebellar Hemisphere	sqtl	4.2e-09	+1.20	11:130123529:C:G

FANTOM5 promoters

10 alternative TSS:

Promoter ID	TPM avg	Samples expressed
117595	283.8265	1825
117594	5.5519	1608
117596	5.4377	1514
117605	2.6495	1098
117606	2.3267	1033
206498	1.4410	943
117607	1.3214	547
117608	0.2899	88
117609	0.0862	24
117615	0.0243	12

Top tissues by expression

showing 100 of 306 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.72	gold quality
choroid plexus epithelium	UBERON:0003911	99.51	gold quality
trigeminal ganglion	UBERON:0001675	99.50	gold quality
medial globus pallidus	UBERON:0002477	99.49	gold quality
monocyte	CL:0000576	99.46	gold quality
lower lobe of lung	UBERON:0008949	99.42	gold quality
descending thoracic aorta	UBERON:0002345	99.40	gold quality
synovial joint	UBERON:0002217	99.38	gold quality
mononuclear cell	CL:0000842	99.36	gold quality
dorsal root ganglion	UBERON:0000044	99.36	gold quality
left lobe of thyroid gland	UBERON:0001120	99.35	gold quality
thyroid gland	UBERON:0002046	99.35	gold quality
leukocyte	CL:0000738	99.34	gold quality
right lung	UBERON:0002167	99.34	gold quality
calcaneal tendon	UBERON:0003701	99.34	gold quality
globus pallidus	UBERON:0001875	99.31	gold quality
thoracic aorta	UBERON:0001515	99.30	gold quality
ascending aorta	UBERON:0001496	99.28	gold quality
right lobe of thyroid gland	UBERON:0001119	99.26	gold quality
cerebellum	UBERON:0002037	99.26	gold quality
cerebellar cortex	UBERON:0002129	99.25	gold quality
cerebellar hemisphere	UBERON:0002245	99.25	gold quality
tendon	UBERON:0000043	99.24	gold quality
cerebellar vermis	UBERON:0004720	99.22	gold quality
upper lobe of lung	UBERON:0008948	99.21	gold quality
upper lobe of left lung	UBERON:0008952	99.20	gold quality
postcentral gyrus	UBERON:0002581	99.19	gold quality
smooth muscle tissue	UBERON:0001135	99.18	gold quality
parietal lobe	UBERON:0001872	99.18	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.18	gold quality
superior vestibular nucleus	UBERON:0007227	99.17	gold quality
aorta	UBERON:0000947	99.16	gold quality
gall bladder	UBERON:0002110	99.16	gold quality
vena cava	UBERON:0004087	99.16	gold quality
nasal cavity epithelium	UBERON:0005384	99.16	gold quality
lung	UBERON:0002048	99.15	gold quality
tendon of biceps brachii	UBERON:0008188	99.15	gold quality
saphenous vein	UBERON:0007318	99.14	gold quality
metanephros cortex	UBERON:0010533	99.13	gold quality
cardia of stomach	UBERON:0001162	99.12	gold quality
mucosa of stomach	UBERON:0001199	99.12	gold quality
right coronary artery	UBERON:0001625	99.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.12	gold quality
islet of Langerhans	UBERON:0000006	99.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.11	gold quality
olfactory bulb	UBERON:0002264	99.10	gold quality
pons	UBERON:0000988	99.09	gold quality
CA1 field of hippocampus	UBERON:0003881	99.08	gold quality
urethra	UBERON:0000057	99.06	gold quality
retina	UBERON:0000966	99.06	gold quality
pigmented layer of retina	UBERON:0001782	99.06	gold quality
popliteal artery	UBERON:0002250	99.06	gold quality
tibial artery	UBERON:0007610	99.06	gold quality
adult mammalian kidney	UBERON:0000082	99.05	gold quality
mammary duct	UBERON:0001765	99.04	gold quality
orbitofrontal cortex	UBERON:0004167	99.04	gold quality
stromal cell of endometrium	CL:0002255	99.03	gold quality
artery	UBERON:0001637	99.03	gold quality
cauda epididymis	UBERON:0004360	99.03	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.03	gold quality
epithelium of mammary gland	UBERON:0003244	99.02	gold quality
pylorus	UBERON:0001166	98.96	gold quality
layer of synovial tissue	UBERON:0007616	98.95	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.94	gold quality
duodenum	UBERON:0002114	98.94	gold quality
seminal vesicle	UBERON:0000998	98.93	gold quality
medulla oblongata	UBERON:0001896	98.93	gold quality
nipple	UBERON:0002030	98.93	gold quality
paraflocculus	UBERON:0005351	98.93	gold quality
ileal mucosa	UBERON:0000331	98.91	gold quality
left ventricle myocardium	UBERON:0006566	98.90	gold quality
superior frontal gyrus	UBERON:0002661	98.89	gold quality
coronary artery	UBERON:0001621	98.88	gold quality
granulocyte	CL:0000094	98.86	gold quality
ventral tegmental area	UBERON:0002691	98.86	gold quality
left coronary artery	UBERON:0001626	98.85	gold quality
trachea	UBERON:0003126	98.85	gold quality
type B pancreatic cell	CL:0000169	98.84	gold quality
rectum	UBERON:0001052	98.83	gold quality
colonic epithelium	UBERON:0000397	98.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.82	gold quality
nasal cavity mucosa	UBERON:0001826	98.80	gold quality
urinary bladder	UBERON:0001255	98.78	gold quality
left uterine tube	UBERON:0001303	98.78	gold quality
germinal epithelium of ovary	UBERON:0001304	98.77	gold quality
upper arm skin	UBERON:0004263	98.76	gold quality
prostate gland	UBERON:0002367	98.75	gold quality
thoracic mammary gland	UBERON:0005200	98.75	gold quality
lower esophagus	UBERON:0013473	98.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.75	gold quality
body of uterus	UBERON:0009853	98.71	gold quality
mammary gland	UBERON:0001911	98.70	gold quality
lateral globus pallidus	UBERON:0002476	98.70	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.69	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.69	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.69	gold quality
hypothalamus	UBERON:0001898	98.68	gold quality
peritoneum	UBERON:0002358	98.67	gold quality
omental fat pad	UBERON:0010414	98.67	gold quality
caecum	UBERON:0001153	98.66	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	3028.45
E-MTAB-6701	yes	121.33
E-HCAD-1	yes	81.46
E-CURD-122	yes	76.51
E-HCAD-6	yes	31.09
E-MTAB-9221	yes	30.34
E-MTAB-9467	yes	29.60
E-CURD-112	yes	23.22
E-MTAB-6678	yes	23.13
E-GEOD-81547	yes	22.49
E-MTAB-9067	yes	17.21
E-GEOD-137537	yes	16.37
E-HCAD-10	yes	16.16
E-GEOD-135922	yes	13.07
E-MTAB-9388	yes	13.03

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thyroid gland	tissue	569.5	high
Retina	tissue	501.5
Choroid plexus	tissue	465.0
Cerebellum	tissue	409.2	high
Lung	tissue	369.2	high
Caudate putamen	tissue	356.5
Kidney	tissue	336.3	high
Liver	tissue	313.2	low
Frontal cortex	tissue	312.4
Placenta	tissue	305.4	high
Parathyroid gland	tissue	274.3	high
Seminal vesicle	tissue	274.2	high
Prostate	tissue	270.0	high
Duodenum	tissue	256.4	high
Postcentral gyrus	tissue	255.3
Heart muscle	tissue	254.3	high
Spinal cord	tissue	249.3
Superior colliculi	tissue	242.5
Pons	tissue	218.0
Small intestine	tissue	213.5	high
Locus coeruleus	tissue	213.5
Cerebral cortex	tissue	211.2	medium
Somatosensory cortex	tissue	211.2
Thalamus	tissue	210.9
Adipose tissue	tissue	203.6	high
Ovary	tissue	201.1	low
Medulla oblongata	tissue	199.9
Substantia nigra	tissue	197.7
Smooth muscle	tissue	197.5	medium
Colon	tissue	196.9	high
Midbrain	tissue	194.5
Occipital cortex	tissue	190.2
Gallbladder	tissue	189.3	high
Urinary bladder	tissue	186.2	high
Bone marrow	tissue	185.5	high
Prefrontal cortex	tissue	182.1
Breast	tissue	180.4	high
Motor cortex	tissue	177.0
Nucleus accumbens	tissue	176.0
Hippocampal formation	tissue	175.5
Hypothalamus	tissue	171.0
Entorhinal cortex	tissue	170.7
Rectum	tissue	166.0	high
Hippocampus	tissue	163.3	high
Temporal cortex	tissue	162.8
Cervix	tissue	160.2	medium
Retrosplenial and cingulate cortex	tissue	159.9
Fallopian tube	tissue	157.8	high
Periaqueductal gray	tissue	156.4
Retrosplenial cortex	tissue	148.1
Insular cortex	tissue	147.7
Olfactory bulb	tissue	143.3
Endometrium 1	tissue	142.7	high
Septum	tissue	142.4
Stomach 1	tissue	141.4	high
Putamen	tissue	138.8
Amygdala	tissue	138.4
Appendix	tissue	136.0	high
Ventral forebrain	tissue	135.9
Epididymis	tissue	130.9	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (376.4), Cerebellar cortex (273.6), Posterior thalamic nucleus (268.6), Lateral hypothalamic area (255.4), Lateral funiculus (white matter) (252.6).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting APLP2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 84 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-7106-5P	99.53	67.47	3574

Functional genomics

gnomAD constraint: pLI 2.66e-08, LOEUF 0.723, missense Z 0.353 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000338167 — one region, missense o/e 1.00.

Literature-anchored findings (GeneRIF, showing 35)

• APLP1 and APLP2 are processed by the gamma-secretase in a Presenilin 1-dependent manner and the extreme carboxyl-terminal fragments produced by this processing (APP-like Intracellular Domain are able to enhance Fe65-dependent gene activation (PMID:12228233)
• crystals of extracellular fragment X3 of a human sperm membrane protein YWK-II/APPH have been grow by the vapour-diffusion method [YWK-II PROTEIN] (PMID:12595709)
• Sustained levels of APP and the elevated levels of APLP2, in spite of the reduced mRNA expression, are due to altered proteolytic processing of these proteins. (PMID:14597230)
• APLP1 and APLP2 and APP are processed similarly to act via the same nuclear target and are regulated by BACE 1 in neurons (PMID:14699153)
• APLP-1 and APLP-2 are processed by alpha- and gamma-secretase-like cleavages, and their intracellular domains can be released by cleavage at epsilon-sites. APLP-2 processing appears to be the most elaborate and to involve alternative cleavage sites. (PMID:14970212)
• The APLP2 gene has no CAGA box, but it does have a GAGA sequence in a location similar to that of the CAGA box in the APP gene. (PMID:15208260)
• Interaction of human and murine Abeta peptides, Abeta40 and Abeta42. Interspecies Abeta aggregates and fibres are readily formed and are more stable than homogenous human fibres. (Amyloid beta 40 and 42) (PMID:15584916)
• APLP2 is shed by disintegrins and metalloproteinases. Overexpression of secretase or TACE in HEK293 cells increases the release of neurotrophic soluble APLP2 severalfold. (PMID:16279945)
• findings show an increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2 and for GSK-3beta in the brains of Alzheimer disease patients (PMID:16645641)
• APLP2 and APP have roles in sperm function (PMID:17405931)
• YWK-II (APLP2 protein) is a G(o)-coupled receptor for Mullerian inhibiting substance in mediating ERK1/2 activation leading to anti-apoptotic activity or cell survival. (PMID:17452623)
• APLP2/MHC association is influenced by multiple domains of the MHC class I heavy chain and by beta(2)m’s effects on the conformation of the heavy chain. (PMID:18452037)
• APLP2 modulates the stability and endocytosis of K(d) molecules (PMID:18641335)
• Coexpression of APP with APLP1 or APLP2 leads to diminished generation of Abeta42 (PMID:19126676)
• APLP2 has a multistep trafficking function that influences the expression of major histocompatibility complex class I molecules at the plasma membrane (PMID:19808674)
• The interaction between APLP2 and ataxin-7 and proteolytic processing of APLP2 may contribute to the pathogenesis of spinocerebellar ataxia type 7. (PMID:20732423)
• APLP-2 (and APLP1) are capable of activating gene transcription via binding to Mint3. (PMID:21178287)
• proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and gamma-secretase (PMID:21695060)
• Regulation of major histocompatibility complex class I molecule expression on cancer cells by amyloid precursor-like protein 2. (PMID:21826533)
• APP and its mammalian homologs, amyloid precursor-like proteins APLP1 and APLP2, participate under physiological conditions via trans-cellular dimerization in synaptogenesis. (PMID:21952790)
• Aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis. (PMID:22641691)
• our discoveries establish a role for APLP2 in the growth of pancreatic cancer cells and show that inhibitors preventing APLP2 cleavage reduce the viability of pancreatic cancer cells. (PMID:22797723)
• amyloid precursor protein-like protein-2, but not amyloid precursor protein, is involved in mediating postendocytic delivery of PCSK9 to lysosomes and is therefore important for PCSK9 function (PMID:23430252)
• Data show that amyloid precursor-like protein 2 (APLP2) expression is elevated in pancreatic cancer metastases. (PMID:25576918)
• APLP1 and APLP2, behave similarly to APP in that they both associate with assembled NMDA receptors in the endoplasmic reticulum (PMID:25683482)
• We conclude that PCSK9 enhances the degradation of the LDLR independently of either APLP2 or sortilin both ex vivo and in mice. (PMID:26085104)
• This paper demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development. (PMID:26313004)
• These findings suggest that the identified APLP2, RRM2, and PRC1 signature could be useful for distinguishing between benign (follicular adenoma) and malignant (follicular carcionma and follicular variant of papillary carcinoma) tumors of the thyroid follicular epithelium. (PMID:27796194)
• the expression of APLP2 might correlate with tumor development and be a prognostic factor for patients with glioblastoma (PMID:29663738)
• our findings indicate that beta2m regulates pancreatic cancer cell migration, and furthermore suggest that APLP2 is an intermediary in this process. (PMID:30810435)
• APLP2 gene polymorphisms are associated with high TC and LDL-C levels in Chinese population in Xinjiang, China. (PMID:32716039)
• APLP2 is predominantly cleaved by beta-secretase and gamma-secretase in the human brain. (PMID:36691315)
• Comprehensive intratumoral heterogeneity landscaping of liver hepatocellular carcinoma and discerning of APLP2 in cancer progression. (PMID:37515494)
• Mycobacterium tuberculosis suppresses APLP2 expression to enhance its survival in macrophage. (PMID:37844466)
• Implication of Amyloid Precursor-like Protein 2 Expression in Cutaneous Squamous Cell Carcinoma Pathogenesis. (PMID:38148084)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aplp2	ENSDARG00000054864
mus_musculus	Aplp2	ENSMUSG00000031996
rattus_norvegicus	Aplp2	ENSRNOG00000047179
drosophila_melanogaster	Appl	FBGN0000108
caenorhabditis_elegans		WBGENE00000149

Paralogs (2): APLP1 (ENSG00000105290), APP (ENSG00000142192)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88047) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased bone mineral density	1
decreased mean corpuscular volume	1
short tibia	1
embryonic growth retardation	1
embryonic lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Cyriopagopus schmidti	B2ZBB8	100.0%	Diamond
Radianthus crispa	C0HJU7	100.0%	Diamond
Heteractis magnifica	C0HK72	100.0%	Diamond
Macaca mulatta	P29216	100.0%	Diamond
Macaca fascicularis	P53601	100.0%	Diamond
Capra hircus	P62756	100.0%	Diamond
Ovis aries	P62757	100.0%	Diamond
Sus scrofa	P79307	100.0%	Diamond
Pan troglodytes	Q5IS80	100.0%	Diamond
Cavia porcellus	Q60495	100.0%	Diamond
Saimiri sciureus	Q95241	100.0%	Diamond
Tabanus yao	C1IBY4	97.4%	Diamond
Pinctada maxima	P86964	94.9%	Diamond
Stichodactyla helianthus	P31713	92.7%	Diamond
Bos taurus	Q08E66	92.0%	Diamond
Mesocricetus auratus	Q60559	86.8%	Diamond
Meriones unguiculatus	Q62577	86.8%	Diamond
Equus caballus	P04365	86.6%	Diamond
Dichotomyctere fluviatilis	O73683	83.9%	Diamond
Takifugu rubripes	O93279	80.4%	Diamond
Anthopleura aff. xanthogrammica	P0DMX0	74.3%	Diamond
Palythoa caribaeorum	P0DQQ9	72.5%	Diamond
Melithaea caledonica	P82968	66.7%	Diamond
Pimpla hypochondriaca	Q8T0W4	66.2%	Diamond
Rhipicephalus microplus	P83606	61.8%	Diamond
Trittame loki	W4VSH9	61.5%	Diamond
Pinctada margaritifera	H2A0N9	58.8%	Diamond
Amblyomma hebraeum	Q5VJG2	57.8%	Diamond
Austrelaps labialis	B2BS84	54.7%	Diamond
Ixodes scapularis	Q964Q0	53.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ZBTB44	protein-coding	29068
ST14	protein-coding	6768
PRDM10-DT	ncRNA	440072
PRDM10	protein-coding	56980
NFRKB	protein-coding	4798
ADAMTS8	protein-coding	11095
ZBTB44-DT	ncRNA	646383

Protein

Protein identifiers

Amyloid beta precursor like protein 2 — Q06481 (reviewed: Q06481)

Alternative names: APPH, Amyloid beta (A4) precursor-like protein 2, Amyloid protein homolog, Amyloid-like protein 2, CDEI box-binding protein, Sperm membrane protein YWK-II

All UniProt accessions (6): A0A140VJE9, Q06481, E9PPD0, E9PQS3, E9PSC7, Q9UED0

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the regulation of hemostasis. The soluble form may have inhibitory properties towards coagulation factors. May interact with cellular G protein signaling pathways. May bind to the DNA 5’-GTCACATG-3’(CDEI box). Inhibits trypsin, chymotrypsin, plasmin, factor XIA and plasma and glandular kallikrein. Modulates the Cu/Zn nitric oxide-catalyzed autodegradation of GPC1 heparan sulfate side chains in fibroblasts.

Subunit / interactions. Interacts with CPEB1. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Interacts (via cytoplasmic domain) with APBB2/FE65L. Interacts (via intracellular domain) with APBB3/FE65L2.

Subcellular location. Cell membrane. Nucleus.

Tissue specificity. Expressed in placenta, brain, heart, lung, liver, kidney and endothelial tissues.

Post-translational modifications. The BPTI/Kunitz inhibitor domain is O-glycosylated.

Similarity. Belongs to the APP family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q06481-1	1	yes
Q06481-2	2
Q06481-3	3
Q06481-4	4
Q06481-5	5
Q06481-6	6

RefSeq proteins (30): NP_001135748, NP_001135749, NP_001135750, NP_001230228, NP_001315611, NP_001315613, NP_001315614, NP_001315615, NP_001369455, NP_001369456, NP_001369457, NP_001369458, NP_001369459, NP_001369460, NP_001369461, NP_001369462, NP_001369463, NP_001369464, NP_001369465, NP_001369466, NP_001369467, NP_001369468, NP_001369469, NP_001369470, NP_001369471, NP_001369472, NP_001369473, NP_001369474, NP_001369475, NP_001633 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002223	Kunitz_BPTI	Domain
IPR008154	Amyloid_glyco_extra	Domain
IPR008155	Amyloid_glyco	Family
IPR011178	Amyloid_glyco_Cu-bd	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015849	Amyloid_glyco_heparin-bd	Domain
IPR019543	APP_amyloid_C	Domain
IPR019744	APP_CUBD_CS	Conserved_site
IPR019745	Amyloid_glyco_intracell_CS	Conserved_site
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR024329	Amyloid_glyco_E2_domain	Domain
IPR036176	E2_sf	Homologous_superfamily
IPR036454	Amyloid_glyco_heparin-bd_sf	Homologous_superfamily
IPR036669	Amyloid_Cu-bd_sf	Homologous_superfamily
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily

Pfam: PF00014, PF02177, PF10515, PF12924, PF12925

UniProt features (58 total): helix 11, disulfide bond 9, splice variant 5, region of interest 4, sequence conflict 4, compositionally biased region 3, binding site 3, strand 3, domain 3, site 2, topological domain 2, turn 2, signal peptide 1, chain 1, short sequence motif 1, modified residue 1, glycosylation site 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
5JBT	Mesotrypsin in complex with cleaved amyloid precursor like protein 2 inhibitor (APLP2)	X-RAY DIFFRACTION	1.4
5TPT	The Crystal Structure of Amyloid Precursor-Like Protein 2 (APLP2) E2 Domain	X-RAY DIFFRACTION	2.42
8RQ6	Solution NMR structure of Amyloid beta precursor like protein 2 TMD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06481-F1	68.87	0.37

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; vesicles

Antibody reliability (HPA): IH approved · IF approved

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 (2)

Position	Role
186	required for cu(2+) reduction
320–321	reactive bond

Ligand- & substrate-binding residues (3)

Position	Role
163	Cu cation
167	Cu cation
184	Cu cation

Post-translational modifications (1)

Type	Positions
Phosphoserine	590

Disulfide bonds (9)

Type	Positions
Disulfide bond	56–80, 91–133, 116–123, 149–203, 160–190, 174–202, 310–360, 319–343, 335–356

Glycosylation sites (1)

Type	Positions
O-linked (xyl…) (chondroitin sulfate) serine	626

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-114608	Platelet degranulation	curated
R-HSA-8957275	Post-translational protein phosphorylation	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	curated
R-HSA-109582	Hemostasis	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-76005	Response to elevated platelet cytosolic Ca2+	—

MSigDB gene sets: 794 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GGGACCA_MIR133A_MIR133B, GOBP_LIPID_MODIFICATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_PINOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_RESPONSE_TO_COLD, LU_IL4_SIGNALING, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT

GO Biological Process (3): G protein-coupled receptor signaling pathway (GO:0007186), axonogenesis (GO:0007409), central nervous system development (GO:0007417)

GO Molecular Function (8): DNA binding (GO:0003677), serine-type endopeptidase inhibitor activity (GO:0004867), heparin binding (GO:0008201), identical protein binding (GO:0042802), transition metal ion binding (GO:0046914), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), membrane (GO:0016020), platelet alpha granule membrane (GO:0031092), extracellular exosome (GO:0070062), platelet alpha granule (GO:0031091)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Metabolism of proteins	2
Response to elevated platelet cytosolic Ca2+	1
Post-translational protein modification	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

30 GO namespaces:

Category	Terms
G protein-coupled receptor activity	1
signal transduction	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
system development	1
animal gross anatomical part developmental process	1
nucleic acid binding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
protein binding	1
metal ion binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cation binding	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
cellular anatomical structure	1
secretory granule membrane	1
platelet alpha granule	1
extracellular vesicle	1
secretory granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
nucleus	CC	direct assay
identical protein binding	MF	physical interaction
serine-type endopeptidase inhibitor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,710 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APLP2	APBB1	O00213	805
APLP2	BACE1	P56817	721
APLP2	APBB2	Q92870	717
APLP2	PSEN2	P49810	641
APLP2	PSEN1	P49768	639
APLP2	NCSTN	Q92542	619
APLP2	PSENEN	Q9NZ42	614
APLP2	APH1A	Q96BI3	609
APLP2	XYLT1	Q86Y38	608
APLP2	APBA1	Q02410	606
APLP2	ADAM10	O14672	598
APLP2	MME	P08473	592
APLP2	APBA2	Q99767	584
APLP2	TNFRSF21	O75509	559
APLP2	APPL1	Q9UKG1	551

IntAct

Human interaction partners of APLP2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

26 partners by confidence:

Partner	Interaction type	MIscore	Records
APBB2	physical association	0.670	1
APBA3	physical association	0.660	1
PIGR	direct interaction	0.560	2
PLXNA4	direct interaction	0.560	2
APBB1	physical association	0.550	1
APBB3	physical association	0.550	1
APLP1	physical association	0.540	2
APP	physical association	0.540	2
DEDD	physical association	0.520	3
CACNA1C	physical association	0.500	1
ITM2B	physical association	0.500	1
MED12	direct interaction	0.440	2
CLEC18A	physical association	0.400	1
H1-2	physical association	0.400	1
SPON1	physical association	0.400	1
RPL26	physical association	0.370	1
ZNF512B	physical association	0.370	1
MED4	association	0.350	1
NSG2	association	0.350	1
UGT3A1	association	0.350	1
JUN	physical association	0.000	3
ETS1	physical association	0.000	2
APBA2	physical association	0.000	1
JUNB	physical association	0.000	1
NFKB1	physical association	0.000	1
NKTR	physical association	0.000	1

BioGRID (156 interactions; top human partners by supporting records): APBB1 (Affinity Capture-MS; 4 records), APBB2 (Affinity Capture-MS; 3 records), APBB3 (Affinity Capture-MS; 3 records), KLK2 (Affinity Capture-MS; 3 records), APBA3 (Affinity Capture-MS; 2 records), BAG6 (Affinity Capture-Western; 2 records), DKKL1 (Affinity Capture-MS; 2 records), FCGRT (Affinity Capture-MS; 2 records), JUN (Two-hybrid; 2 records), KRAS (Proximity Label-MS; 2 records), PTPN2 (Affinity Capture-MS; 2 records), VAV1 (Affinity Capture-MS; 2 records), AHSA1 (Affinity Capture-MS), APOD (Affinity Capture-MS), B3GAT1 (Proximity Label-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
MAPK8	up-regulates	APLP2	phosphorylation
CDK1	unknown	APLP2	phosphorylation
PRKCA	unknown	APLP2	phosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
APLP2-MED12-MED23-MED4 complex (incomplete Mediator complex)	4	MED4, APLP2, MED12, MED23

Ligand–receptor pairs (CellPhoneDB) (2)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

2 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
PIGR	ligand	Signaling by Amyloid-like protein
PLXNA4	ligand	Signaling by Amyloid-like protein

Disease & clinical

Genetic variants

Variant evidence for APLP2: 159 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	130
Likely benign	4
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 41 predictions of 1,417):

Position(s)	Effect	Δscore	Sites
11:130109423–130109424	acceptor_gain	1.0000	2
11:130109427–130109428	acceptor_loss	1.0000	6
11:130109603–130109604	donor_loss	1.0000	6
11:130110534–130110535	acceptor_gain	1.0000	2
11:130110536–130110537	acceptor_loss	1.0000	6
11:130110662–130110663	donor_loss	1.0000	5
11:130120704–130120705	acceptor_loss	1.0000	5
11:130120819–130120820	donor_loss	1.0000	4
11:130121811–130121812	donor_loss	1.0000	4
11:130122292	acceptor_gain	1.0000

AlphaMissense

1,648 missense substitutions predicted likely pathogenic (of 5,013 scored), across 401 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M745	9	0.899	0.994
M405	9	0.886	0.977
H456	8	0.998	0.999
H387	8	0.994	0.998
H513	8	0.993	0.999
H506	8	0.992	0.999
D503	8	0.991	0.998
N348	8	0.988	0.999
H510	8	0.988	0.999
H532	8	0.986	0.997
F390	8	0.978	1.000
N752	8	0.977	0.997
F350	8	0.974	0.998
F338	8	0.962	0.997
H401	8	0.935	0.994
N349	8	0.924	0.997
N346	8	0.915	0.993
S543	8	0.905	0.999
D518	8	0.884	0.985
D732	8	0.884	0.963

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9.06e-06
Glioblastoma Multiforme (validation)	unfavorable	0.000338
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000366
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000817

Disease associations

OMIM: gene MIM:104776 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST006585_566	Blood protein levels	2e-33
GCST006585_2739	Blood protein levels	4e-20

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	7
Tretinoin	affects cotreatment, increases expression, increases metabolic processing, increases secretion	6
Copper	affects binding, increases response to substance, affects localization	3
Tobacco Smoke Pollution	increases expression, affects expression, decreases expression	3
(+)-JQ1 compound	increases expression	2
Decitabine	affects methylation, increases expression	2
Arsenic Trioxide	increases expression, affects cotreatment	2
Vehicle Emissions	increases abundance, increases expression	2
Lead	affects expression, affects splicing, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Genistein	increases reaction, decreases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
deoxynivalenol	decreases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
nivalenol	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
di-n-butylphosphoric acid	affects expression	1
Am 580	increases expression	1
N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide	decreases reaction, increases secretion, decreases secretion	1
CGP 52608	affects binding, increases reaction	1
K 7174	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
N-benzyloxycarbonyl-valyl-leucyl-leucinal	decreases secretion	1
dorsomorphin	increases expression, affects cotreatment	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
Rosiglitazone	increases expression	1
Resveratrol	affects cotreatment, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SC93	HAP1 APLP2 (-) 1	Cancer cell line	Male
CVCL_SC94	HAP1 APLP2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.