PKMYT1

Official Full Name

protein kinase, membrane associated tyrosine/threonine 1

Organism

Homo sapiens

GeneID

9088

Background

This gene encodes a member of the serine/threonine protein kinase family. The encoded protein is a membrane-associated kinase that negatively regulates the G2/M transition of the cell cycle by phosphorylating and inactivating cyclin-dependent kinase 1. The activity of the encoded protein is regulated by polo-like kinase 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

Synonyms

MYT1; PPP1R126;

Bio Chemical Class

Kinase

Protein Sequence

MLERPPALAMPMPTEGTPPPLSGTPIPVPAYFRHAEPGFSLKRPRGLSRSLPPPPPAKGSIPISRLFPPRTPGWHQLQPRRVSFRGEASETLQSPGYDPSRPESFFQQSFQRLSRLGHGSYGEVFKVRSKEDGRLYAVKRSMSPFRGPKDRARKLAEVGSHEKVGQHPCCVRLEQAWEEGGILYLQTELCGPSLQQHCEAWGASLPEAQVWGYLRDTLLALAHLHSQGLVHLDVKPANIFLGPRGRCKLGDFGLLVELGTAGAGEVQEGDPRYMAPELLQGSYGTAADVFSLGLTILEVACNMELPHGGEGWQQLRQGYLPPEFTAGLSSELRSVLVMMLEPDPKLRATAEALLALPVLRQPRAWGVLWCMAAEALSRGWALWQALLALLCWLWHGLAHPASWLQPLGPPATPPGSPPCSLLLDSSLSSNWDDDSLGPSLSPEAVLARTVGSTSTPRSRCTPRDALDLSDINSEPPRGSFPSFEPRNLLSLFEDTLDPT

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Detailed Information

PKMYT1 (Protein Kinase Membrane-Associated Tyrosine/Threonine 1) is located on human chromosome 16p13.3 and encodes a membrane-associated tyrosine/threonine protein kinase belonging to the WEE kinase family. Alternative splicing generates multiple transcript variants, producing proteins with a conserved kinase domain: the N-terminal region forms an ATP-binding cleft surrounded by five β-sheets and an αC-helix, while the C-terminal region mainly consists of α-helices, including a critical activation loop. Notably, the N-terminal contains a glycine-rich flexible P-loop, which dynamically adjusts its conformation according to the catalytic state and ligand binding, forming the top surface of the ATP-binding pocket. This structural arrangement enables PKMYT1 to precisely regulate substrate phosphorylation.

Figure 1. Diagram of PKMYT1 kinase structure highlighting its three major domains—N-terminal regulatory domain (NRD), central kinase domain (KD), and C-terminal regulatory domain (CRD)—with key phosphorylation sites and domain-specific interactions. (Yang M, et al., 2024)

Within the cell cycle regulatory network, PKMYT1 functions as a key mitotic “brake.” As a major regulator of the G2/M checkpoint, it phosphorylates CDK1 (Cyclin-Dependent Kinase 1) at Thr14 and Tyr15, inhibiting the CDK1-cyclin B complex. This phosphorylation retains the complex in the cytoplasm, preventing nuclear entry and mitotic initiation. Compared with the related kinase WEE1, PKMYT1 shows stronger selectivity for Thr14 phosphorylation, while Tyr15 phosphorylation is weaker and possibly indirect. This specificity allows PKMYT1 to play a unique role during DNA damage repair: upon DNA damage, PKMYT1 is activated by the ATR-CHK1 pathway, prolonging CDK1 inhibition to provide time for repair. Once repair is complete, phosphatase CDC25 removes inhibitory phosphates, releasing CDK1 activity to drive mitotic entry.

Beyond cell cycle regulation, PKMYT1 participates in Golgi fragmentation. During prophase, it phosphorylates the Golgi matrix protein GM130, triggering Golgi disassembly into vesicles to ensure proper organelle segregation during mitosis. This function aligns with PKMYT1’s subcellular localization: N-terminal myristoylation targets it to the Golgi membrane and the ER-Golgi intermediate compartment (ERGIC). PKMYT1 activity is further regulated by post-translational modifications: PLK1 phosphorylates Ser75 to promote proteasomal degradation, forming a positive feedback loop for CDK1 activation, whereas PP1 phosphatase antagonizes this process to stabilize PKMYT1 levels.

Role in Tumorigenesis

PKMYT1 is aberrantly overexpressed in multiple cancers, promoting tumor progression by interfering with cell cycle checkpoints. TCGA data indicate significant upregulation in breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma, colorectal cancer, and bladder cancer. Overexpression mechanisms include gene amplification (~15% of PDAC), transcriptional activation by estrogen-ERα signaling in ER-positive breast cancer, and Wnt/β-catenin pathway activation in colorectal cancer.

Mechanistically, PKMYT1 drives cancer through tissue-specific signaling networks. In hepatocellular and colorectal cancers, PKMYT1 activates the β-catenin/TGF axis, promoting epithelial-mesenchymal transition (EMT) and enhancing invasiveness. Phosphorylation of GSK3β by PKMYT1 reduces β-catenin degradation, increasing β-catenin/TCF transcription and upregulating EMT factors such as SNAIL and TWIST. In non-small cell lung cancer, PKMYT1 downregulates the NOTCH1-p21-HES1 module to release proliferation inhibition. In esophageal squamous cell carcinoma, PKMYT1 phosphorylates AKT at Ser473, activating the AKT/mTOR pathway to promote proliferation and migration.

Clinically, PKMYT1 expression correlates with tumor stage, size, and patient age. In breast cancer, late-stage tumors (III-IV) show 2.3-fold higher PKMYT1 than early-stage tumors, and tumors >5 cm express 3.1-fold more PKMYT1 than ≤2 cm tumors. High PKMYT1 expression associates with poorer survival: five-year overall survival decreases by ~35%, and the hazard ratio reaches 1.22. Similar correlations are observed in PDAC, where high PKMYT1 expression predicts shorter median survival and increased recurrence risk.

Synthetic Lethality and Targeted Therapy

PKMYT1 is a synthetic lethal target in tumors with G1/S checkpoint defects, such as those with CCNE1 amplification, FBXW7 mutation, or CDK2 amplification. In these tumors, G2/M checkpoint dependence makes PKMYT1 inhibition induce catastrophic DNA damage and apoptosis while sparing normal cells. RP-6306 (Replimib) is a highly selective PKMYT1 inhibitor in clinical trials, showing potent tumor suppression in CCNE1-amplified ovarian cancer PDX models and synergistic effects with PARP inhibitors. CRISPR-Cas9 functional genomic screens have validated PKMYT1 as essential in PDAC, with knockout leading to G2/M arrest, γH2AX accumulation, and caspase-3-dependent apoptosis. Combination therapies with ATR inhibitors further enhance antitumor effects.

Resistance Mechanisms and Strategies

Adaptive resistance to PKMYT1 inhibition occurs via compensatory PLK1 upregulation and cyclin B1 elevation, restoring CDK1 activity. Combining PKMYT1 inhibitors with PLK1 or CDK1 inhibitors can overcome resistance. Biomarkers such as replication stress score and FBXW7 mutation status predict sensitivity to PKMYT1-targeted therapies.

Clinical Translation

PKMYT1-targeted therapies are advancing in clinical trials. RP-6306 has demonstrated manageable toxicity, with intermittent dosing reducing hematologic side effects. Allosteric inhibitors, such as XY-03, offer selective disruption of PKMYT1-CDK1 interaction with lower bone marrow toxicity. Future directions include biomarker refinement, optimized drug delivery using tumor microenvironment-responsive carriers, and combination strategies with immune checkpoint inhibitors to exploit PKMYT1 inhibition-induced DNA damage. PKMYT1 inhibition holds promise as a precision therapy for tumors with specific genetic backgrounds, particularly CCNE1-amplified cancers.

Reference

Yang M, Xiang H, Luo G. Targeting Protein Kinase, Membrane-Associated Tyrosine/Threonine 1 (PKMYT1) for Precision Cancer Therapy: From Discovery to Clinical Trial. J Med Chem. 2024 Oct 24;67(20):17997-18016.
Schmidt M, Rohe A, Platzer C, et al. Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases. Molecules. 2017 Nov 23;22(12):2045.

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