PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions. PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway. PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors.
An overview of Pim
Human phosphatidyl inositol mannoside kinases (Pim kinases) are a family of serine/threonine kinases composed of three members: Pim-1, Pim-2 and Pim-3. These kinases share the ability to transform lymphoma cells, although it is not clear that they have completely overlapping biochemical mechanisms of action. Pim kinases proto oncogenes regulate several signaling pathways which are directly related to the development of numerous malignancies. The Pim-1 kinase isoform has been specifically reported in the last two decades for its direct role in tumor genesis process in various hematological malignancies, such as lymphoma and acute myeloid leukemia.
Major types of Pim
The Pim serine/threonine kinases include three isoforms, Pim-1, Pim-2, and Pim-3, that are implicated in the growth and progression of hematological malignancies, prostate cancer, and, in the case of Pim-3, in precancerous and cancerous lesions of the pancreas, liver, colon, and stomach. Pim-1 and Pim-2 have been shown to cooperate with c-Myc in inducing lymphoma, and prostate cancer, and in the absence of Pim-1 and Pim-2, Pim-3 is activated in c-Myc-induced lymphomas.
Inhibition of Pim
Because of the importance of the Pim kinase signal transduction pathway in the progression of various cancers, multiple groups have developed small-molecule inhibitors of this kinase family. Researchers have identified unique benzylidene-thiazolidine-2-4-diones that inhibit Pim kinase activity in vitro at nanomolar concentrations, and in culture induce apoptosis of human leukemic cells and synergize with rapamycin to downregulate 4EBP1 phosphorylation and inhibit cell growth. The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione was identified by screening to be a Pim-1 inhibitor and was found to attenuate the autophosphorylation of tagged Pim-1 in intact cells.
Pim and diseases
Cancer becomes one of the most mortal diseases during recent years in spite of rapid advances made in diagnostic and the treatment procedures. Most cancer-associated proteases are intracellular enzymes and some of them turn out to be overexpressed in cancer cells. The Pim serine protein kinases, potential causative enzymes, are reliable diagnostic markers for cancers because they play crucial roles in the growth and progression of multiple cancer types. Among Pim protein kinases, Pim-1 kinase is richly expressed and found to be secreted by diverse kinds of cancers, including head and neck cancer, prostate cancer, breast cancer, and gastric carcinoma.
Ying-Wei Lin (2016). A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma, 115, 824-834.