Pim Kinase

Supporting information

Pim kinases are constitutively active serine/threonine kinases that promote growth factor-independent proliferation by phosphorylating, and thus inhibiting, a range of cellular proteins. Both Pim-1 and Pim-2 kinase are serine/threonine kinases that are involved in the control of cell growth, differentiation and apoptosis.

Pim-1 kinase is a serine/threonine kinase that is involved in the control of cell growth, differentiation and apoptosis. It is expressed at high levels in the testes, prostate, oral epithelia, hippocampus and hematopoietic tissues, and is expressed at low or undetectable levels in other tissues. In the fetal liver and spleen, expression of Pim-1 kinase is high, but the protein is undetectable here in the adult.

Pim-2 kinase is also a serine/threonine kinase, and displays similar activity to Pim-1 kinase. In particular, it promotes cell survival by phosphorylating Bad protein.

Substrates of Pim-1 include nuclear adapter protein 100, which enhances the transcriptional activity of the proto-oncogene c-Myb. Cdc25A is phosphorylated by Pim-1 kinase, which amplifies its positive effect on cells to transit through the G1 and S phases. Other Pim-1 kinase substrates include p21Waf, an inhibitor of cell cycle progression; heterochromatin protein 1 (HP-1); PAP-1 and SOCS proteins. Pim-1-mediated phosphorylation of HP-1 may represent an important epigenetic regulatory mechanism of chromatin condensation and gene expression. Pim-2 kinase prevents apoptosis by inhibiting caspase 3 and phosphorylating Bad protein, preventing its inhibitory interaction with the antiapoptotic protein Bcl-XL.

Pim-2 kinase also increases NF-κB activity, possibly by inhibiting IκB. Both Pim-1 and Pim-2 kinase phosphorylate p27Kip1, the cyclin-dependent kinase inhibitor, overcoming G1 arrest.

Due to their constitutive activity, expression of Pim kinases is regulated at the level of transcription, translation and degradation. Pim-1 kinase expression can be induced by a variety of cytokines, mitogens and hormones, such as GM-CSF, interleukins, erythropoietin, IFN-γ and prolactin. At the transcriptional level, IL-2 can release the transcriptional attenuation of the Pim-1 kinase gene leading to increased protein expression. Pim-2 kinase levels are linked to IL-3 availability. Eukaryotic translation initiation factor 4E (eIF-4E) enhances Pim-1 kinase expression at the translational level and PP2A decreases Pim-1 kinase levels. Pim-1 kinase autophoshorylation is thought to occur and the enzyme is stabilized by interactions with Hsp90α and β. In addition, the PI 3-K signaling pathway is involved in Pim-1 kinase regulation and the JAK2/STAT5 pathway plays an important role in mediating cytokine and growth factor-stimulated Pim-1 kinase expression.

Both Pim-1 and Pim-2 kinase have been found to be overexpressed or mutated in a variety of human tumors including B cell lymphomas, leukemias, prostate cancer and oral cancer. Synergism between Pim kinases and the oncogenic Myc genes has been shown to contribute to transformation by inhibiting apoptosis, and upregulation of Pim-1 and Pim-2 kinase is associated with cell survival. Furthermore, dysregulation of the Pim-1 kinase gene alters differentiation and proliferation, and enhances the transforming potential of its substrates such as Cdc25A. Pim-1 and Pim-3 also help maintain the embryonic stem cell identity by supporting ESC self-renewal, and inhibiting differentiation and apoptosis.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
PIM1 Human PIM1 NM_002648 P11309
Mouse Pim1 NM_008842 P06803
Rat Pim1 NM_017034 P26794
PIM2 Human PIM2 NM_006875 U77735
Mouse Pim2 NM_138606 Q62070
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Literature for Pim Kinase

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