PIM3

Official Full Name

Pim-3 proto-oncogene, serine/threonine kinase

Organism

Homo sapiens

GeneID

415116

Background

The protein encoded by this gene belongs to the Ser/Thr protein kinase family, and PIM subfamily. This gene is overexpressed in hematological and epithelial tumors and is associated with MYC coexpression. It plays a role in the regulation of signal transduction cascades, contributing to both cell proliferation and survival, and provides a selective advantage in tumorigenesis. [provided by RefSeq, Jun 2012]

Synonyms

pim-3;

Bio Chemical Class

Kinase

Protein Sequence

MLLSKFGSLAHLCGPGGVDHLPVKILQPAKADKESFEKAYQVGAVLGSGGFGTVYAGSRIADGLPVAVKHVVKERVTEWGSLGGATVPLEVVLLRKVGAAGGARGVIRLLDWFERPDGFLLVLERPEPAQDLFDFITERGALDEPLARRFFAQVLAAVRHCHSCGVVHRDIKDENLLVDLRSGELKLIDFGSGALLKDTVYTDFDGTRVYSPPEWIRYHRYHGRSATVWSLGVLLYDMVCGDIPFEQDEEILRGRLLFRRRVSPECQQLIRWCLSLRPSERPSLDQIAAHPWMLGADGGVPESCDLRLCTLDPDDVASTTSSSESL

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

PIM3 (Proto-oncogene Serine/Threonine-Protein Kinase 3) is located on human chromosome 22q13.2 and is the most recently identified member of the PIM kinase family. It encodes a protein of 326 amino acids with a molecular weight of approximately 35 kDa. PIM3 lacks regulatory domains and anchors to the plasma membrane via a C-terminal hydrophobic motif. Similar to PIM1, PIM3 exhibits constitutive kinase activity, but its tissue distribution differs markedly: it is highly expressed in the liver, pancreas, and brain, while its expression in the hematopoietic system is limited. Pathologically, PIM3 overexpression is observed in 60% of hepatocellular carcinoma, 45% of pancreatic ductal adenocarcinoma, and 38% of gastric cancer, and it is closely associated with EBV-related lymphomas.

Figure 1. Schematic representation of the human PIM gene family, highlighting exon organization, UTR motifs, alternative translation sites, and the conserved serine/threonine kinase activity of all isoforms. (Atalay P, et al., 2024)

Biological Function and Signaling Regulation

PIM3 coordinates cell survival and metabolic adaptation through phosphorylation-mediated signaling networks. It inhibits apoptosis by phosphorylating BAD at Ser112, which releases BAD from Bcl-xL and suppresses mitochondrial apoptotic pathways. PIM3 also regulates metabolic reprogramming by negatively modulating AMPK activity, stabilizing MYC protein, and promoting glycolysis, while attenuating ERK1/2 phosphorylation to fine-tune insulin secretion. Additionally, PIM3 enhances protein synthesis by phosphorylating 4EBP1 at Thr37/46, thereby releasing eIF4E and increasing the translation efficiency of oncogenic proteins. During angiogenesis, PIM3 in endothelial progenitor cells (EPCs) responds to hypoxia-inducible factor HIF-1α and phosphorylates GSK3β at Ser9 to activate β-catenin signaling, driving EPC homing to ischemic myocardium and promoting collateral circulation formation.

Clinical Significance and Disease Associations

Abnormal PIM3 expression is closely linked to solid tumor progression and therapy resistance. In gastric cancer, immunohistochemistry reveals a PIM3 positivity rate of 90% in tumors compared to 16% in adjacent tissue, correlating with differentiation, lymph node metastasis, and venous invasion. In hepatocellular carcinoma, PIM3 is overexpressed in over 60% of cases, and its inhibition via AZD1208 derivatives induces tumor cell apoptosis and suppresses xenograft growth. Beyond oncology, in myocardial infarction models, EPCs overexpressing PIM3 increase capillary density in infarcted regions by 2.1-fold and improve cardiac function by 40% (left ventricular ejection fraction).

Therapeutic Strategies

Current strategies targeting PIM3 include pan-PIM inhibitors such as PIM447 (LGH447), which showed a 17% objective response rate in phase I trials for multiple myeloma. Dual inhibitors like JP11646 (targeting both PIM and FLT3) enhance gemcitabine efficacy threefold in pancreatic cancer models. Combination therapies also show promise; in EBV-positive lymphomas, PIM3 inhibitors combined with PD-1 blockade can reverse T cell exhaustion and increase complete remission rates.

Research Challenges and Future Directions

The primary challenge in PIM3-targeted therapy is its functional redundancy with PIM1 and PIM2, as well as its role in normal metabolic regulation. Future directions include developing tissue-selective delivery methods using nanocarriers such as liver-targeted GalNAc conjugates to reduce off-target effects, identifying predictive biomarkers such as EBV infection status or MYC co-expression profiles, and designing novel molecules like allosteric inhibitors targeting the PIM3–14-3-3σ interaction or dual-function degraders (PIM3-PROTAC). With deeper understanding of PIM3’s role in tumor metabolic microenvironments, it is poised to become a key target for combination immunotherapy and metabolic modulation.

Reference

Atalay P, Ozpolat B. PIM3 Kinase: A Promising Novel Target in Solid Cancers. Cancers (Basel). 2024 Jan 26;16(3):535.
Wu J, Chu E, Kang Y. PIM Kinases in Multiple Myeloma. Cancers (Basel). 2021 Aug 26;13(17):4304.

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