PALS2

Summary

PALS2 (protein associated with LIN7 2, MAGUK p55 family member, HGNC:18167) is a protein-coding gene on chromosome 7p15.3, encoding Protein PALS2 (Q9NZW5).

Members of the peripheral membrane-associated guanylate kinase (MAGUK) family function in tumor suppression and receptor clustering by forming multiprotein complexes containing distinct sets of transmembrane, cytoskeletal, and cytoplasmic signaling proteins. All MAGUKs contain a PDZ-SH3-GUK core and are divided into 4 subfamilies, DLG-like (see DLG1; MIM 601014), ZO1-like (see TJP1; MIM 601009), p55-like (see MPP1; MIM 305360), and LIN2-like (see CASK; MIM 300172), based on their size and the presence of additional domains. MPP6 is a member of the p55-like MAGUK subfamily (Tseng et al., 2001 [PubMed 11311936]).

Source: NCBI Gene 51678 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_001303037

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18167
Approved symbol	PALS2
Name	protein associated with LIN7 2, MAGUK p55 family member
Location	7p15.3
Locus type	gene with protein product
Status	Approved
Aliases	VAM-1, p55T
Ensembl gene	ENSG00000105926
Ensembl biotype	protein_coding
OMIM	606959
Entrez	51678

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000222644, ENST00000396475, ENST00000409761, ENST00000426450, ENST00000430180, ENST00000432190, ENST00000464384, ENST00000472674, ENST00000896217, ENST00000896218, ENST00000896219, ENST00000927836, ENST00000927837, ENST00000927838, ENST00000927839, ENST00000927840, ENST00000927841, ENST00000927842, ENST00000927843, ENST00000927844, ENST00000927845

RefSeq mRNA: 2 — MANE Select: NM_001303037 NM_001303037, NM_016447

CCDS: CCDS5388

Canonical transcript exons

ENST00000222644 — 12 exons

Exon	Start	End
ENSE00000673953	24663590	24663721
ENSE00000831999	24623666	24623784
ENSE00001375943	24573452	24573593
ENSE00003384137	24666021	24666089
ENSE00003489310	24665588	24665687
ENSE00003531399	24649612	24649764
ENSE00003556537	24668499	24668660
ENSE00003579483	24680392	24680520
ENSE00003604225	24641716	24641868
ENSE00003631889	24679131	24679333
ENSE00003706930	24687438	24694193
ENSE00003788852	24650485	24650712

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 95.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.4596 / max 157.8898, expressed in 1463 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77698	2.4871	985
77697	1.5345	877
77696	1.0249	519
77705	0.9677	449
77699	0.4327	231
77702	0.0071	4
77703	0.0056	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.40	gold quality
adrenal tissue	UBERON:0018303	93.37	gold quality
islet of Langerhans	UBERON:0000006	90.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.48	gold quality
tibia	UBERON:0000979	89.71	gold quality
left testis	UBERON:0004533	89.60	gold quality
gall bladder	UBERON:0002110	89.41	gold quality
right testis	UBERON:0004534	88.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.64	gold quality
testis	UBERON:0000473	88.24	gold quality
cortical plate	UBERON:0005343	87.47	gold quality
sural nerve	UBERON:0015488	86.82	gold quality
tendon	UBERON:0000043	84.36	gold quality
sperm	CL:0000019	83.49	gold quality
colonic epithelium	UBERON:0000397	83.33	gold quality
pancreas	UBERON:0001264	82.48	gold quality
male germ cell	CL:0000015	81.99	gold quality
cartilage tissue	UBERON:0002418	81.72	gold quality
stromal cell of endometrium	CL:0002255	80.96	gold quality
ventricular zone	UBERON:0003053	80.57	gold quality
gastrocnemius	UBERON:0001388	79.97	gold quality
body of pancreas	UBERON:0001150	79.57	gold quality
muscle of leg	UBERON:0001383	79.39	gold quality
tibial nerve	UBERON:0001323	79.34	gold quality
ganglionic eminence	UBERON:0004023	78.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.95	gold quality
descending thoracic aorta	UBERON:0002345	77.74	gold quality
bone marrow cell	CL:0002092	76.35	gold quality
thoracic aorta	UBERON:0001515	75.58	gold quality
metanephros cortex	UBERON:0010533	75.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

269 targeting PALS2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 4)

• Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons. (PMID:33034629)
• MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus. (PMID:35902094)
• Elevated MPP6 expression correlates with an unfavorable prognosis, angiogenesis and immune evasion in hepatocellular carcinoma. (PMID:37207207)
• Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy. (PMID:38565536)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	pals2b	ENSDARG00000029761
danio_rerio	pals2a	ENSDARG00000056892
mus_musculus	Pals2	ENSMUSG00000038388
rattus_norvegicus	Pals2	ENSRNOG00000021579
drosophila_melanogaster	CASK	FBGN0013759
drosophila_melanogaster	metro	FBGN0050021
drosophila_melanogaster	vari	FBGN0250785
caenorhabditis_elegans		WBGENE00002991
caenorhabditis_elegans	magu-3	WBGENE00016841
caenorhabditis_elegans		WBGENE00021914

Paralogs (7): PALS1 (ENSG00000072415), MPP4 (ENSG00000082126), MPP2 (ENSG00000108852), MPP1 (ENSG00000130830), CASK (ENSG00000147044), MPP7 (ENSG00000150054), MPP3 (ENSG00000161647)

Protein

Protein identifiers

Protein PALS2 — Q9NZW5 (reviewed: Q9NZW5)

Alternative names: MAGUK p55 subfamily member 6, Membrane protein, palmitoylated 6, Veli-associated MAGUK 1

All UniProt accessions (6): Q9NZW5, B8ZZG1, C9J4Q3, C9JGI8, F8WCD2, R4GNA8

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with CADM1. Interacts with the LIN7 proteins.

Subcellular location. Membrane.

Tissue specificity. Abundant in testis, brain, and kidney with lower levels detectable in other tissues.

Similarity. Belongs to the MAGUK family.

RefSeq proteins (2): NP_001289966, NP_057531 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR004172	L27_dom	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR014775	L27_C	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035603	MPP6_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036892	L27_dom_sf	Homologous_superfamily
IPR050716	MAGUK	Family

Pfam: PF00595, PF00625, PF02828, PF07653

UniProt features (8 total): domain 5, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZW5-F1	83.91	0.52

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 (1): 500

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 232 (showing top): FREAC2_01, RORA1_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, BROWNE_HCMV_INFECTION_16HR_UP, TGACCTY_ERR1_Q2, AAAYRNCTG_UNKNOWN, CEBP_Q2, MUELLER_PLURINET, FREAC3_01, MODULE_285, RYTAAWNNNTGAY_UNKNOWN, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, LYF1_01, AACTTT_UNKNOWN

GO Biological Process (1): protein-containing complex assembly (GO:0065003)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane (GO:0016020), extracellular exosome (GO:0070062), organelle (GO:0043226)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular component assembly	1
protein-containing complex organization	1
binding	1
membrane	1
cell periphery	1
anchoring junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

1756 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PALS2	LIN7A	O14910	965
PALS2	CADM1	Q9BY67	895
PALS2	CADM4	Q8NFZ8	888
PALS2	CADM3	Q8N126	878
PALS2	STYK1	Q6J9G0	762
PALS2	NECTIN3	Q9NQS3	703
PALS2	PATJ	Q8NI35	701
PALS2	EPB41	P11171	627
PALS2	NECTIN1	Q15223	622
PALS2	PVR	P15151	585
PALS2	NECTIN2	Q92692	572
PALS2	AFDN	P55196	552
PALS2	LIN7C	Q9NUP9	549
PALS2	EPB41L2	O43491	548
PALS2	TJP1	Q07157	536

IntAct

440 interactions, top by confidence:

A	B	Type	Score
LIN7C	PALS2	psi-mi:“MI:0915”(physical association)	0.800
LIN7B	PALS2	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LIN7A	PALS2	psi-mi:“MI:0915”(physical association)	0.670
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
MPP2	LIN7A	psi-mi:“MI:0914”(association)	0.640
CDA	LIN7A	psi-mi:“MI:0914”(association)	0.640
SLC20A1	LIN7A	psi-mi:“MI:0914”(association)	0.640
MILR1	INPPL1	psi-mi:“MI:0914”(association)	0.640
CFTR	PALS2	psi-mi:“MI:0407”(direct interaction)	0.570
NSUN2	LIN7A	psi-mi:“MI:0914”(association)	0.530
MINDY3	UBB	psi-mi:“MI:0914”(association)	0.530
LIN7C	ABLIM1	psi-mi:“MI:0914”(association)	0.530
LIN7B	CASK	psi-mi:“MI:0914”(association)	0.530
TRPS1	MTA2	psi-mi:“MI:0914”(association)	0.530
MPP2	ABLIM1	psi-mi:“MI:0914”(association)	0.530
C1orf174	AHCYL1	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PALS2	NRXN3	psi-mi:“MI:0407”(direct interaction)	0.440
GYPC	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
PALS2	CNTNAP2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (115): MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), THOP1 (Two-hybrid), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS), MPP6 (Affinity Capture-MS)

ESM2 similar proteins: A4D1E9, A4IHT9, A6QLJ3, A6QPU5, A9JTX2, B1H116, B3RXR7, E1BMP7, E3TDS3, I0IUP3, O23617, O80738, P06801, P13697, P31754, P32296, P51530, Q0E671, Q16798, Q1LZ83, Q29K06, Q2KI15, Q2TAA5, Q3MHG6, Q4V7N2, Q503J2, Q5M8V6, Q5R7Z6, Q5RDW1, Q5U528, Q5VV42, Q6DHF7, Q6NS23, Q6NS26, Q6P4Y0, Q6PI48, Q7SYM0, Q8BIP0, Q8BMF3, Q8C3X4

Diamond homologs: A6QQZ7, A8KBF6, A9CB74, B4F7E7, D3ZAA9, E2QY99, G5ECY0, O14936, O34328, O70589, O88910, O88954, P0C0M9, P15454, P31006, P31007, P44310, P46195, P49697, P54936, P65219, P65220, P65221, P70175, P70290, P72648, P93757, P99176, Q00013, Q13368, Q14168, Q15700, Q16774, Q17QN6, Q182S8, Q24210, Q2FHM9, Q2G1U0, Q2QPW1, Q2S8R2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 183 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
Neurexins and neuroligins	9	14.3×	8e-06
Assembly and cell surface presentation of NMDA receptors	6	12.3×	1e-03
NRAGE signals death through JNK	6	8.9×	4e-03
RHOQ GTPase cycle	6	8.8×	4e-03
Cardiac conduction	7	6.1×	7e-03
RHOA GTPase cycle	10	6.0×	1e-03
CDC42 GTPase cycle	10	5.8×	1e-03
RHO GTPase cycle	11	5.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of synaptic transmission, glutamatergic	5	18.5×	9e-03
positive regulation of excitatory postsynaptic potential	5	15.6×	9e-03
adult behavior	5	13.8×	1e-02
protein-containing complex assembly	9	6.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2849 predictions. Top by Δscore:

Variant	Effect	Δscore
7:24623645:ATGTT:A	acceptor_gain	1.0000
7:24623646:T:G	acceptor_gain	1.0000
7:24623746:GGAAT:G	donor_gain	1.0000
7:24641712:TCAG:T	acceptor_loss	1.0000
7:24641713:CA:C	acceptor_loss	1.0000
7:24641714:A:AG	acceptor_gain	1.0000
7:24641714:A:AT	acceptor_loss	1.0000
7:24641714:AG:A	acceptor_gain	1.0000
7:24641715:G:A	acceptor_gain	1.0000
7:24641715:G:GA	acceptor_gain	1.0000
7:24641715:GGC:G	acceptor_gain	1.0000
7:24641715:GGCT:G	acceptor_gain	1.0000
7:24641715:GGCTC:G	acceptor_gain	1.0000
7:24641865:CCAG:C	donor_loss	1.0000
7:24641866:CAGGT:C	donor_loss	1.0000
7:24641867:AGGTA:A	donor_loss	1.0000
7:24641868:GG:G	donor_loss	1.0000
7:24649610:A:AG	acceptor_gain	1.0000
7:24649611:G:GG	acceptor_gain	1.0000
7:24650481:ATAG:A	acceptor_gain	1.0000
7:24650483:AG:A	acceptor_gain	1.0000
7:24650484:GG:G	acceptor_gain	1.0000
7:24650484:GGGT:G	acceptor_gain	1.0000
7:24663719:CAGG:C	donor_loss	1.0000
7:24663720:AGG:A	donor_loss	1.0000
7:24663722:GTT:G	donor_loss	1.0000
7:24663723:T:A	donor_loss	1.0000
7:24665705:A:AG	donor_gain	1.0000
7:24665705:A:G	donor_gain	1.0000
7:24665709:G:GG	donor_gain	1.0000

AlphaMissense

3563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:24649616:T:C	L92P	1.000
7:24650528:G:C	R156P	1.000
7:24650585:T:A	I175N	1.000
7:24663629:G:C	D231H	1.000
7:24663630:A:T	D231V	1.000
7:24663713:T:A	W259R	1.000
7:24663713:T:C	W259R	1.000
7:24663715:G:C	W259C	1.000
7:24663715:G:T	W259C	1.000
7:24663716:T:A	W260R	1.000
7:24663716:T:C	W260R	1.000
7:24665622:T:C	L273P	1.000
7:24665628:C:A	P275Q	1.000
7:24665630:A:C	S276R	1.000
7:24665631:G:T	S276I	1.000
7:24665632:C:A	S276R	1.000
7:24665632:C:G	S276R	1.000
7:24665640:T:C	L279P	1.000
7:24665652:G:C	R283T	1.000
7:24665653:A:C	R283S	1.000
7:24665653:A:T	R283S	1.000
7:24668580:G:A	G345E	1.000
7:24668595:G:A	G350D	1.000
7:24668611:A:C	K355N	1.000
7:24668611:A:T	K355N	1.000
7:24679263:G:A	G416E	1.000
7:24687588:T:A	W533R	1.000
7:24687588:T:C	W533R	1.000
7:24623741:T:C	L25P	0.999
7:24641849:T:C	L84P	0.999

dbSNP variants (sampled 300 via entrez): RS1000013694 (7:24633222 G>A), RS1000029014 (7:24648673 A>C), RS1000040235 (7:24664580 T>C), RS1000060351 (7:24594113 C>G), RS1000064769 (7:24612589 G>A), RS1000134588 (7:24655649 T>C,G), RS1000135220 (7:24618735 G>T), RS1000197820 (7:24617519 T>C), RS1000208725 (7:24617957 A>C), RS1000267076 (7:24611611 T>A,C), RS1000286080 (7:24628472 C>G), RS1000300666 (7:24683814 G>C), RS1000316847 (7:24595821 C>G), RS1000324385 (7:24684865 A>G), RS1000324896 (7:24658541 T>C)

Disease associations

OMIM: gene MIM:606959 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Estradiol	increases expression, increases reaction	2
bisphenol F	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide	increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Cisplatin	affects expression	1
Cytarabine	decreases expression	1
Diethylstilbestrol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Phenobarbital	affects expression	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

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