MASTL

Summary

MASTL (microtubule associated serine/threonine kinase like, HGNC:19042) is a protein-coding gene on chromosome 10p12.1, encoding Serine/threonine-protein kinase greatwall (Q96GX5). Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. It is a common-essential gene (DepMap: required in 97.7% of cancer cell lines).

This gene encodes a microtubule-associated serine/threonine kinase. Mutations at this locus have been associated with autosomal dominant thrombocytopenia, also known as thrombocytopenia-2. Alternatively spliced transcript variants have been described for this locus.

Source: NCBI Gene 84930 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal thrombocytopenia with normal platelets (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 212 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_001172303

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19042
Approved symbol	MASTL
Name	microtubule associated serine/threonine kinase like
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14813, THC2, Gwl
Ensembl gene	ENSG00000120539
Ensembl biotype	protein_coding
OMIM	608221
Entrez	84930

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 17 protein_coding

ENST00000342386, ENST00000375940, ENST00000375946, ENST00000477034, ENST00000896814, ENST00000896815, ENST00000933941, ENST00000933942, ENST00000933943, ENST00000933944, ENST00000933945, ENST00000933946, ENST00000933947, ENST00000933948, ENST00000969651, ENST00000969652, ENST00000969653

RefSeq mRNA: 7 — MANE Select: NM_001172303 NM_001172303, NM_001172304, NM_001320756, NM_001320757, NM_001372029, NM_001372030, NM_032844

CCDS: CCDS53502, CCDS53503, CCDS7153

Canonical transcript exons

ENST00000375940 — 12 exons

Exon	Start	End
ENSE00000000187	27155352	27155612
ENSE00000000188	27186379	27187953
ENSE00000985396	27158549	27158686
ENSE00000985397	27159619	27159758
ENSE00000985398	27161094	27161182
ENSE00000985399	27165064	27165170
ENSE00000985400	27165389	27165539
ENSE00000985401	27167102	27167274
ENSE00000985403	27180953	27181066
ENSE00000985404	27181480	27181581
ENSE00003732538	27169944	27171083
ENSE00003741234	27173118	27173259

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 91.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9427 / max 159.8847, expressed in 1746 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104442	5.3987	1257
104440	4.2272	1445
104443	0.9481	436
104441	0.3688	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	91.47	gold quality
oocyte	CL:0000023	88.81	gold quality
ventricular zone	UBERON:0003053	88.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.45	gold quality
amniotic fluid	UBERON:0000173	87.97	gold quality
ganglionic eminence	UBERON:0004023	86.01	gold quality
calcaneal tendon	UBERON:0003701	83.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.12	gold quality
epithelial cell of pancreas	CL:0000083	80.73	silver quality
upper arm skin	UBERON:0004263	80.44	silver quality
cartilage tissue	UBERON:0002418	79.22	gold quality
adrenal tissue	UBERON:0018303	78.95	gold quality
bone marrow	UBERON:0002371	78.72	gold quality
bone marrow cell	CL:0002092	78.50	gold quality
monocyte	CL:0000576	77.41	gold quality
leukocyte	CL:0000738	77.33	gold quality
stromal cell of endometrium	CL:0002255	77.25	gold quality
vermiform appendix	UBERON:0001154	77.15	gold quality
esophagus mucosa	UBERON:0002469	76.86	gold quality
placenta	UBERON:0001987	76.85	gold quality
lower esophagus mucosa	UBERON:0035834	76.40	gold quality
smooth muscle tissue	UBERON:0001135	76.33	gold quality
islet of Langerhans	UBERON:0000006	76.32	gold quality
gingival epithelium	UBERON:0001949	76.21	silver quality
granulocyte	CL:0000094	76.14	gold quality
palpebral conjunctiva	UBERON:0001812	76.13	gold quality
germinal epithelium of ovary	UBERON:0001304	76.10	gold quality
descending thoracic aorta	UBERON:0002345	75.94	gold quality
rectum	UBERON:0001052	75.84	gold quality
skin of leg	UBERON:0001511	75.70	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	249.13
E-MTAB-6678	yes	7.80
E-CURD-112	yes	4.40
E-MTAB-6142	no	169.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting MASTL, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 26)

• A novel missense mutation in the human gene FLJ14813 is associated with autosomal dominant thrombocytopenia (PMID:12890928)
• A paper that narrows the identity of the gene for autosomal dominant thrombocytopenia (THC2) to FLJ14813. The mutation is present in all affected people across three generations while is absent in unaffected family members & 94 random blood donors. (PMID:12890928)
• MASTL enhances cyclin B1-Cdk1-dependent mitotic phosphorylation events, directing mitotic entry, anaphase and cytokinesis in human cells. (PMID:20818157)
• results identify Gwl as a member of the AGC family of kinases that appears to be regulated by unique mechanisms and that differs from the other members of this family (PMID:21444715)
• Studies indicate that mutations in three different genes within the THC2 locus have been associated with congenital thrombocytopenia, including a mutation in MASTL. (PMID:22102272)
• Taken together our results suggest a hierarchy of phosphatases coordinating Greatwall, Ensa/ARPP19 and Cdk substrate dephosphorylation during mitotic exit. (PMID:24391510)
• Mastl upregulation is involved in cancer progression and tumor recurrence after initial cancer therapy (PMID:25373736)
• data demonstrate that GWL acts in a pathway with PP2A which is essential for prophase I exit and metaphase I microtubule assembly in mouse oocytes. (PMID:25472593)
• Data show that siRNA knockdown of Forkhead box M1 (FOXM1) or microtubule-associated serine/threonine kinase-like (MASTL) induces radiosensitivity in non-small cell lung cancer (NSCLC). (PMID:25808837)
• Thus, GWL is a human oncoprotein that promotes the hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies. (PMID:26613407)
• Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma. (PMID:26616283)
• Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression. (PMID:26653855)
• Using mathematical modelling, this paper confirms that deactivation of MASTL is essential for mitotic exit. (PMID:26872783)
• these results established that precise control of MASTL is essential to couple DNA damage to mitosis through the rate of mitotic entry and APC/C activation. (PMID:26923777)
• E2F8 can shorten cisplatin induced G2/M arrest by promoting MASTL mediated mitotic progression in ER+ breast cancer cells, conferring drug resistance. (PMID:28605876)
• The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. (PMID:29229993)
• MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival. (PMID:29743597)
• Data show that MASTL expression increases in colon cancer (CC) across all cancer stages. Also, increased levels of MASTL associated with high-risk disease and poor prognosis. Further, its silencing induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth. Functional analysis revealed that MASTL expression facilitates CC progression and chemoresistance by promoting the beta-catenin/Wnt signa… (PMID:30068336)
• MASTL depletion impaired thyroid tumor cell proliferation and increased the percentage of cells presenting nuclear anomalies, which are indicative of mitotic catastrophe. (PMID:30445205)
• AKT Regulates Mitotic Progression of Mammalian Cells by Phosphorylating MASTL, Leading to Protein Phosphatase 2A Inactivation. (PMID:32123010)
• MASTL promotes cell contractility and motility through kinase-independent signaling. (PMID:32311005)
• MASTL: A novel therapeutic target for Cancer Malignancy. (PMID:32692487)
• Knockdown of Microtubule Associated Serine/threonine Kinase Like Expression Inhibits Gastric Cancer Cell Growth and Induces Apoptosis by Activation of ERK1/2 and Inactivation of NF-kappaB Signaling. (PMID:33582914)
• Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers. (PMID:33627787)
• MASTL regulates EGFR signaling to impact pancreatic cancer progression. (PMID:34331012)
• SILAC kinase screen identifies potential MASTL substrates. (PMID:35732702)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mastl	ENSDARG00000055566
mus_musculus	Mastl	ENSMUSG00000026779
rattus_norvegicus	Mastl	ENSRNOG00000054474
drosophila_melanogaster	gwl	FBGN0260399

Paralogs (13): MAST4 (ENSG00000069020), MAST2 (ENSG00000086015), MAST3 (ENSG00000099308), SGK2 (ENSG00000101049), SGK3 (ENSG00000104205), DMPK (ENSG00000104936), MAST1 (ENSG00000105613), SGK1 (ENSG00000118515), LATS1 (ENSG00000131023), LATS2 (ENSG00000150457), STK32B (ENSG00000152953), STK32C (ENSG00000165752), STK32A (ENSG00000169302)

Protein

Protein identifiers

Serine/threonine-protein kinase greatwall — Q96GX5 (reviewed: Q96GX5)

Alternative names: Microtubule-associated serine/threonine-protein kinase-like

All UniProt accessions (2): A0A087WUU7, Q96GX5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at ‘Ser-62’ and ‘Ser-67’, respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Nucleus. Cleavage furrow.

Post-translational modifications. Phosphorylation at Thr-741 by CDK1 during M phase activates its kinase activity. Maximum phosphorylation occurs in prometaphase.

Disease relevance. Defects in MASTL may play a role in the pathogenesis of thrombocytopenia, a disorder defined by reduced number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting.

Miscellaneous. Reduced levels of MASTL by RNAi causes mitotic abnormalities that consist of delay in G(2) phase and slow chromosome condensation. Cells that enter and progress through mitosis often fail to completely separate their sister chromatids in anaphase leading to the formation of 4N G(1) cells subsequent to failure of cytokinesis.

Similarity. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96GX5-1	1	yes
Q96GX5-2	2
Q96GX5-3	3

RefSeq proteins (7): NP_001165774, NP_001165775, NP_001307685, NP_001307686, NP_001358958, NP_001358959, NP_116233 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR037638	MASTL_STKc	Domain
IPR050236	Ser_Thr_kinase_AGC	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (61 total): modified residue 17, helix 11, strand 8, sequence variant 5, sequence conflict 4, region of interest 3, domain 2, binding site 2, splice variant 2, turn 2, compositionally biased region 2, chain 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8V5H	X-RAY DIFFRACTION	2.74
5LOH	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96GX5-F1	54.88	0.21

Functional residue map

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

Catalytic / active sites (1): 156 (proton acceptor)

Ligand- & substrate-binding residues (2): 62; 41–49

Post-translational modifications (17): 1, 207, 222, 293, 370, 453, 519, 552, 556, 631, 657, 668, 722, 725, 741, 875, 878

Mutagenesis-validated functional residues (1):

Position	Phenotype
72	hyperactive form.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2465910	MASTL Facilitates Mitotic Progression

MSigDB gene sets: 196 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, FISCHER_G1_S_CELL_CYCLE, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_CELL_CYCLE_PHASE_TRANSITION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOCC_MICROTUBULE_ORGANIZING_CENTER, SHEPARD_BMYB_MORPHOLINO_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_ORGANELLE_FISSION, GOBP_REGULATION_OF_CELL_CYCLE, GOCC_CENTROSOME, E4F1_Q6, GOBP_DNA_DAMAGE_RESPONSE, GOBP_MITOTIC_CELL_CYCLE, GOBP_CELL_CYCLE_G2_M_PHASE_TRANSITION

GO Biological Process (9): G2/M transition of mitotic cell cycle (GO:0000086), DNA damage response (GO:0006974), female meiosis II (GO:0007147), regulation of mitotic cell cycle (GO:0007346), intracellular signal transduction (GO:0035556), cell division (GO:0051301), regulation of cell cycle (GO:0051726), protein phosphorylation (GO:0006468), meiotic cell cycle (GO:0051321)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), kinase activity (GO:0016301), transmembrane transporter binding (GO:0044325), protein phosphatase 2A binding (GO:0051721), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), transferase activity (GO:0016740)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), centrosome (GO:0005813), microtubule cytoskeleton (GO:0015630), cleavage furrow (GO:0032154), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitotic Prophase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitotic cell cycle	2
intracellular anatomical structure	2
cell cycle	2
protein kinase activity	2
cellular anatomical structure	2
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
cellular response to stress	1
meiosis II	1
female meiotic nuclear division	1
female gamete generation	1
meiotic cell cycle	1
regulation of cell cycle	1
signal transduction	1
cellular process	1
regulation of cellular process	1
phosphorylation	1
protein modification process	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transferase activity, transferring phosphorus-containing groups	1
protein binding	1
protein phosphatase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
cytoskeleton	1
cell division site	1
plasma membrane region	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MASTL	ENSA	O43768	982
MASTL	ARPP19	P56211	979
MASTL	PPP2R2D	Q66LE6	959
MASTL	PPP2R1A	P30153	656
MASTL	PPP2CA	P05323	627
MASTL	PPP2R2A	P50409	599
MASTL	SGO1	Q5FBB7	586
MASTL	PTTG1	O95997	575
MASTL	REC8	O95072	573
MASTL	PPP1R1B	Q9UD71	562
MASTL	SGO2	Q562F6	551
MASTL	EEF2	P13639	506
MASTL	STAG2	Q8N3U4	469
MASTL	RAD21	O60216	469
MASTL	CTDP1	Q9Y5B0	450

IntAct

22 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
PLK1	C1orf226	psi-mi:“MI:0914”(association)	0.560
PHAF1	PSMG1	psi-mi:“MI:0914”(association)	0.530
RPS6KA1	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
Dynll1		psi-mi:“MI:0915”(physical association)	0.400
MASTL	MED26	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
TLK2	IGKV1D-13	psi-mi:“MI:0914”(association)	0.350
PIP	RBM47	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
CCT8L2	DVL2	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
TCTE1	DVL2	psi-mi:“MI:2364”(proximity)	0.270
BUD13	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
ZRANB2	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (76): IGO1 (Biochemical Activity), MASTL (Affinity Capture-MS), MASTL (Proximity Label-MS), CDK18 (Affinity Capture-MS), SLC1A5 (Affinity Capture-MS), SSFA2 (Affinity Capture-MS), TAP2 (Affinity Capture-MS), MED26 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), UBN1 (Affinity Capture-MS), DERL2 (Affinity Capture-MS), MRPL2 (Affinity Capture-MS), EPB41L5 (Affinity Capture-MS), FASTKD5 (Affinity Capture-MS), CEP85 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K3AV08, A6NIR3, A7J1T0, A7J1T2, A7KAX9, A7MBB4, A8X775, B1WAR9, D2HXI8, E1C2I2, E2RJI4, M0R5D6, O01700, O13839, O35607, O43283, P35831, P46200, P46934, P51960, P83510, Q05209, Q05935, Q0WPH8, Q13873, Q14693, Q1HKZ5, Q1LXZ9, Q2PFD7, Q3TEL6, Q5R8X7, Q5VUJ5, Q5VW22, Q60592, Q60DG4, Q61IS6, Q62770, Q6DBX4, Q6GPD0, Q6INH1

Diamond homologs: A0A7J6K7I9, A0A7J6K7Y0, A0A7J6KD88, A8X775, B1WAR9, C4YRB7, D2HXI8, E1C2I2, E9PSL7, G1X456, G5EGQ3, M3TYT0, O00506, O01583, O01700, O14578, O54874, O61267, O75116, O77819, O80902, O88643, O97627, P05131, P0CY23, P0CY24, P13677, P21146, P25098, P26817, P26818, P32865, P34100, P35465, P38070, P48562, P49025, P49673, P54265, P70335

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CyclinA2/CDK2	“up-regulates activity”	MASTL	phosphorylation
PP2CA_R1A_R2A	“down-regulates activity”	MASTL	dephosphorylation
CTDP1	“down-regulates activity”	MASTL	dephosphorylation
AKT1	“up-regulates activity”	MASTL	phosphorylation
CyclinB/CDK1	“up-regulates activity”	MASTL	phosphorylation
MASTL	“up-regulates activity”	MASTL	phosphorylation
CDK1	“up-regulates activity”	MASTL	phosphorylation
MASTL	“up-regulates activity”	ARPP19	phosphorylation
MASTL	“up-regulates activity”	ENSA	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	26
Benign	37

Top pathogenic / likely-pathogenic (0)

SpliceAI

1854 predictions. Top by Δscore:

Variant	Effect	Δscore
10:27155568:A:T	donor_gain	1.0000
10:27158538:A:AG	acceptor_gain	1.0000
10:27158547:A:AG	acceptor_gain	1.0000
10:27158547:AG:A	acceptor_gain	1.0000
10:27158548:G:GA	acceptor_gain	1.0000
10:27158548:GG:G	acceptor_gain	1.0000
10:27158548:GGT:G	acceptor_gain	1.0000
10:27158548:GGTT:G	acceptor_gain	1.0000
10:27158682:ACTTG:A	donor_gain	1.0000
10:27158683:CTTG:C	donor_gain	1.0000
10:27158684:TTG:T	donor_gain	1.0000
10:27158687:G:GG	donor_gain	1.0000
10:27159613:T:TA	acceptor_gain	1.0000
10:27159617:A:AC	acceptor_loss	1.0000
10:27159618:G:A	acceptor_loss	1.0000
10:27159755:ACAGG:A	donor_loss	1.0000
10:27159757:AG:A	donor_loss	1.0000
10:27159758:GG:G	donor_loss	1.0000
10:27159760:T:G	donor_loss	1.0000
10:27161092:A:AG	acceptor_gain	1.0000
10:27161093:G:GG	acceptor_gain	1.0000
10:27165057:T:G	acceptor_gain	1.0000
10:27165166:GATTT:G	donor_gain	1.0000
10:27165171:G:GG	donor_gain	1.0000
10:27165503:GACAC:G	donor_gain	1.0000
10:27186377:A:G	acceptor_gain	1.0000
10:27157612:T:G	acceptor_gain	0.9900
10:27158539:T:G	acceptor_gain	0.9900
10:27158542:A:AG	acceptor_gain	0.9900
10:27158547:AGGTT:A	acceptor_gain	0.9900

AlphaMissense

5852 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:27155562:T:C	F46L	1.000
10:27155564:C:A	F46L	1.000
10:27155564:C:G	F46L	1.000
10:27161150:A:T	D174V	1.000
10:27155530:T:C	F35S	0.999
10:27155550:A:C	S42R	0.999
10:27155552:C:A	S42R	0.999
10:27155552:C:G	S42R	0.999
10:27155556:G:C	G44R	0.999
10:27155565:G:A	G47R	0.999
10:27155565:G:C	G47R	0.999
10:27155565:G:T	G47W	0.999
10:27155566:G:A	G47E	0.999
10:27155566:G:T	G47V	0.999
10:27155578:T:C	L51P	0.999
10:27155605:C:A	A60E	0.999
10:27155612:G:C	K62N	0.999
10:27155612:G:T	K62N	0.999
10:27158616:T:C	L85P	0.999
10:27161096:A:C	D156A	0.999
10:27161096:A:T	D156V	0.999
10:27161117:T:C	L163P	0.999
10:27161149:G:C	D174H	0.999
10:27161150:A:C	D174A	0.999
10:27161150:A:G	D174G	0.999
10:27161151:T:A	D174E	0.999
10:27161151:T:G	D174E	0.999
10:27155548:T:A	I41N	0.998
10:27155557:G:A	G44D	0.998
10:27155562:T:A	F46I	0.998

dbSNP variants (sampled 300 via entrez): RS1000057271 (10:27182649 A>C), RS1000062740 (10:27185317 CCT>C), RS1000072928 (10:27175649 G>A), RS1000265402 (10:27158550 T>C,G), RS1000340718 (10:27172319 A>G), RS1000466004 (10:27187373 T>G), RS1000618617 (10:27180880 C>A), RS1000896558 (10:27165599 T>A,C), RS1001095222 (10:27159119 G>A), RS1001184326 (10:27167612 A>T), RS1001231791 (10:27182303 T>C), RS1001257587 (10:27175333 C>T), RS1001270139 (10:27157044 C>G), RS1001700595 (10:27153934 C>T), RS1001711607 (10:27174973 T>G)

Disease associations

OMIM: gene MIM:608221 | disease phenotypes: MIM:188000

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal thrombocytopenia with normal platelets	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
thrombocytopenia	Limited	AD

Mondo (3): thrombocytopenia 2 (MONDO:0008555), thrombocytopenia (MONDO:0002049), (MONDO:0015679)

Orphanet (1): Hereditary thrombocytopenia with normal platelets (Orphanet:268322)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004607_115	Plateletcrit	1.000000e-10
GCST004750_30	Squamous cell lung carcinoma	2.000000e-06
GCST90002400_699	Plateletcrit	3.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C536519	Thrombocytopenia chromosome breakage (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105826 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — MAST family

ChEMBL bioactivities

41 potent at pChembl≥5 of 41 total, top 41 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.74	Ki	0.018	nM	CHEMBL5573613
10.70	Ki	0.02	nM	CHEMBL5575224
10.68	Ki	0.021	nM	CHEMBL5567557
10.54	Ki	0.029	nM	CHEMBL5575089
10.54	Ki	0.029	nM	CHEMBL5562696
10.52	Ki	0.03	nM	CHEMBL5572095
10.30	Ki	0.05	nM	CHEMBL5567557
10.22	Ki	0.06	nM	CHEMBL6159974
10.05	Ki	0.09	nM	CHEMBL6141877
10.05	Ki	0.09	nM	CHEMBL6152544
9.92	Ki	0.12	nM	CHEMBL6161435
9.66	Ki	0.22	nM	CHEMBL6150078
9.59	Ki	0.26	nM	CHEMBL6145957
9.54	Ki	0.29	nM	CHEMBL6134243
9.43	Ki	0.37	nM	CHEMBL6151068
9.39	Ki	0.41	nM	CHEMBL6109191
8.96	IC50	1.1	nM	CHEMBL6132886
8.62	IC50	2.4	nM	CHEMBL6159974
8.55	IC50	2.8	nM	CHEMBL6161435
8.43	Ki	3.7	nM	CHEMBL6160170
8.42	Ki	3.8	nM	CHEMBL6133523
8.36	Ki	4.4	nM	CHEMBL6147539
8.31	IC50	4.9	nM	CHEMBL6132886
8.15	IC50	7	nM	CHEMBL5567557
7.92	IC50	12	nM	CHEMBL6141877
7.82	IC50	15	nM	CHEMBL6150078
7.80	IC50	16	nM	CHEMBL6151068
7.64	IC50	23	nM	CHEMBL6147539
7.51	Ki	31	nM	CHEMBL6146920
7.44	IC50	36	nM	CHEMBL6134243
7.36	IC50	44	nM	CHEMBL6145957
7.34	Ki	46	nM	CHEMBL6145815
7.29	IC50	51	nM	CHEMBL6109191
7.23	IC50	59	nM	CHEMBL6152544
7.12	IC50	75	nM	CHEMBL6146920
7.00	IC50	100	nM	CHEMBL6133523
6.79	IC50	163	nM	CHEMBL6160170
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.93	IC50	1182	nM	CHEMBL6145815

PubChem BioAssay actives

6 with measured affinity, of 33 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-N-[4-[(1S)-1-(methylamino)propyl]-2-pyridinyl]-3-(3-methyltriazol-4-yl)-2,7-naphthyridine-1,6-diamine	2094780: Inhibition of N-terminal FLAG-tagged full-length recombinant human MASTL expressed in baculovirus infected insect cells using AQT0693 as substrate incubated for 120 mins in presence of ATP by fluorescence based assay	ki	<0.0001	uM
6-N-[4-[(2S)-2-aminobutan-2-yl]-2-pyridinyl]-3-(3-methyltriazol-4-yl)-2,7-naphthyridine-1,6-diamine	2094780: Inhibition of N-terminal FLAG-tagged full-length recombinant human MASTL expressed in baculovirus infected insect cells using AQT0693 as substrate incubated for 120 mins in presence of ATP by fluorescence based assay	ki	<0.0001	uM
6-N-[4-[(2R)-2-(methylamino)butan-2-yl]-2-pyridinyl]-3-(3-methyltriazol-4-yl)-2,7-naphthyridine-1,6-diamine	2094780: Inhibition of N-terminal FLAG-tagged full-length recombinant human MASTL expressed in baculovirus infected insect cells using AQT0693 as substrate incubated for 120 mins in presence of ATP by fluorescence based assay	ki	<0.0001	uM
6-N-[4-[(2S)-2-(methylamino)butan-2-yl]-2-pyridinyl]-3-(3-methyltriazol-4-yl)-2,7-naphthyridine-1,6-diamine	2094780: Inhibition of N-terminal FLAG-tagged full-length recombinant human MASTL expressed in baculovirus infected insect cells using AQT0693 as substrate incubated for 120 mins in presence of ATP by fluorescence based assay	ki	<0.0001	uM
6-N-[4-[(S)-cyclopropyl(methylamino)methyl]-2-pyridinyl]-3-(3-methyltriazol-4-yl)-2,7-naphthyridine-1,6-diamine	2094780: Inhibition of N-terminal FLAG-tagged full-length recombinant human MASTL expressed in baculovirus infected insect cells using AQT0693 as substrate incubated for 120 mins in presence of ATP by fluorescence based assay	ki	<0.0001	uM
6-N-[4-[(2S)-2-aminobutan-2-yl]-5-methyl-2-pyridinyl]-3-(3-methyltriazol-4-yl)-2,7-naphthyridine-1,6-diamine	2094780: Inhibition of N-terminal FLAG-tagged full-length recombinant human MASTL expressed in baculovirus infected insect cells using AQT0693 as substrate incubated for 120 mins in presence of ATP by fluorescence based assay	ki	<0.0001	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, increases expression	4
bisphenol A	decreases expression, increases expression, affects cotreatment	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
Air Pollutants	decreases expression, increases abundance	2
Arsenic	affects methylation, increases methylation	2
Estradiol	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
monomethylarsonous acid	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
Dasatinib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Azathioprine	decreases expression	1
Caffeine	decreases phosphorylation	1
Cannabidiol	increases expression	1
Cisplatin	increases expression	1
Coal	decreases expression, increases abundance	1
Coumestrol	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

44 unique, capped per target: 44 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4034399	Binding	Inhibition of MASTL ATP binding site (unknown origin) at 10 uM	Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT