PIM1

Official Full Name

Pim-1 proto-oncogene, serine/threonine kinase

Organism

Homo sapiens

GeneID

5292

Background

The protein encoded by this gene belongs to the Ser/Thr protein kinase family, and PIM subfamily. This gene is expressed primarily in B-lymphoid and myeloid cell lines, and is overexpressed in hematopoietic malignancies and in prostate cancer. It plays a role in signal transduction in blood cells, contributing to both cell proliferation and survival, and thus provides a selective advantage in tumorigenesis. Both the human and orthologous mouse genes have been reported to encode two isoforms (with preferential cellular localization) resulting from the use of alternative in-frame translation initiation codons, the upstream non-AUG (CUG) and downstream AUG codons (PMIDs:16186805, 1825810).[provided by RefSeq, Aug 2011]

Synonyms

PIM;

Bio Chemical Class

Kinase

Protein Sequence

MLLSKINSLAHLRAAPCNDLHATKLAPGKEKEPLESQYQVGPLLGSGGFGSVYSGIRVSDNLPVAIKHVEKDRISDWGELPNGTRVPMEVVLLKKVSSGFSGVIRLLDWFERPDSFVLILERPEPVQDLFDFITERGALQEELARSFFWQVLEAVRHCHNCGVLHRDIKDENILIDLNRGELKLIDFGSGALLKDTVYTDFDGTRVYSPPEWIRYHRYHGRSAAVWSLGILLYDMVCGDIPFEHDEEIIRGQVFFRQRVSSECQHLIRWCLALRPSDRPTFEEIQNHPWMQDVLLPQETAEIHLHSLSPGPSK

Open

Disease

Acute myeloid leukaemia, Non-small-cell lung cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

PIM1 (Proto-oncogene Serine/Threonine-Protein Kinase) is located on human chromosome 6p21.2 and encodes a constitutively active serine/threonine kinase. The gene exhibits unique translational regulation: its mRNA 5′UTR contains a non-AUG (CUG) start codon, producing a 44 kDa cytoplasmic isoform and a 33 kDa nuclear isoform. PIM1 activity does not require phosphorylation for activation; instead, its stability is tightly controlled through binding to HSP90, which prevents ubiquitin-proteasome-mediated degradation. In normal tissues, PIM1 is enriched in hematopoietic stem cells, prostate epithelium, and neurons. Pathologically, PIM1 is overexpressed in approximately 70% of diffuse large B-cell lymphomas, 50% of prostate cancers, and 30% of pancreatic cancers, often co-amplified with MYC to form a cooperative oncogenic network.

Figure 1. AlphaFold-predicted structures of murine and human PIM1 showing 313 amino acids each, with per-residue confidence scores (pLDDT) indicating model reliability. (Yang X, et al., 2024)

Biological Functions and Signaling Networks

PIM1 regulates cell survival, proliferation, and metabolism through phosphorylation of downstream targets. It inhibits apoptosis by phosphorylating BAD (Ser112), FOXO3a (Ser318), and MAP3K5, blocking caspase cascades and mitochondrial apoptotic pathways. It promotes cell cycle progression via phosphorylation of CDC25A (Ser76) and CDKN1B/p27 (Thr157/198), facilitating G1/S and G2/M transitions. PIM1 also reprograms metabolism by activating mTORC1 signaling through DEPDC5 inhibition and inducing chemotherapeutic drug efflux via ABCG2 phosphorylation (Thr362). Additionally, PIM1 modulates the immune microenvironment; phosphorylation of GBP1 (Ser363) retains it in the cytoplasm, dampening innate immune responses. During aging, PIM1 activates the C/EBPδ pathway in PDGFRα⁺ mesenchymal progenitors, driving adipogenic differentiation, leading to intramuscular fat infiltration and sarcopenia.

Clinical Relevance and Disease Mechanisms

Aberrant PIM1 expression is associated with multiple malignancies and treatment resistance. In clear cell renal cell carcinoma (ccRCC), tissue microarray analysis shows PIM1 positivity in 82% of cases, correlating with TNM stage. Nuclear PIM1 phosphorylates Smad2/3 (Ser245/249) and c-Myc (Thr58/62), synergistically activating EMT transcription factors such as ZEB1 and Snail, promoting metastasis. In cervical squamous cell carcinoma, PIM1 expression is significantly higher than in the normal cervix and correlates with lymph node metastasis and clinical stage. In aging skeletal muscle, PIM1 expression increases 2.3-fold in older mice, driving mesenchymal progenitors toward adipocyte differentiation and causing a 40% reduction in muscle strength.

Targeted Intervention Strategies

Therapeutic approaches against PIM1 include small molecule inhibitors, such as SGI-1776, which inhibits EMT and reduces cell migration by 60% in ccRCC models, and AZD1208, which induces apoptosis in hematologic malignancies and overcomes FLT3 inhibitor resistance. In age-related muscle disorders, Pim1 knockout mice show a 50% reduction in intramuscular fat and maintain muscle strength comparable to young mice, suggesting PIM1 inhibitors like SGI-1776 could serve as potential sarcopenia therapies. Combination therapies have shown promise: PIM1 inhibitors with HIF-2α inhibitor Belzutifan synergistically suppress VEGF signaling in ccRCC, and in lymphomas, combined with BCL-2 inhibitor Venetoclax, they enhance apoptotic induction.

Translational Challenges and Future Directions

PIM1-targeted therapy faces two main obstacles: the conserved kinase ATP-binding pocket, which limits inhibitor selectivity due to similarity with kinases such as CK2, and compensatory activation by PIM2/PIM3. Future research will focus on developing allosteric inhibitors targeting PIM1–substrate interactions, epigenetic modulation via CRISPR/dCas9-mediated promoter silencing, and patient-stratified combination therapies, particularly for MYC-amplified tumors with PIM1/mTOR co-inhibition. With PROTAC degraders like PIM1-PROTAC entering preclinical evaluation, the field is poised for significant advances.

Reference

Yang X, Liu C, Lei Y, et al. PIM1 signaling in immunoinflammatory diseases: an emerging therapeutic target. Front Immunol. 2024 Sep 20;15:1443784.
Decker S, Finter J, Forde AJ, et al. PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). Mol Cancer Ther. 2014 May;13(5):1231-45.

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