Pim family of protein kinases: Structure,functions, and roles in hematopoietic malignancies

Phosphorylation is the universal regulatory mechanism of key physiological processes, such as development, cell differentiation, proliferation, survival, and malignant transformation. The review considers serine/threonine protein kinases of the Pim (proviral integration of Moloney virus) family, which were initially discovered in experimental lymphomas. Data on the gene structure, evolution, functions, and substrates of Pim protein kinases are provided. The role in the biology of hematopoietic malignancies is discussed for Pim-1 as the major isoform. Pim-1 is a proproliferative and prosurvival protein kinase. Pim-1 is constitutively active owing to autophosphorylation, and its downstream partners positively regulate the cell cycle. Pim-1 cooperates with the c-Myc oncoprotein in leukemogenesis and, like the Akt protein kinase, prevents cell death. Thus, Pim kinases are regarded as new therapeutic targets. An original test system for a phenotypic screening of Pim inhibitors is presented. In this test system, the growth of a genetically engineered Escherichia coli strain in the presence of kanamycin depends on the phosphorylation of aminoglycoside 3′-phosphotransferase VIII by Pim-1, and pharmacological inhibition of this phosphorylation increases bacterial cell lysis.