Structure and Substrate Specificity of the Pim-1 Kinase

Bullock, Alex N.; Debreczeni, J.; Amos, A.; Knapp, Stefan; Turk, Benjamin E.

doi:10.1074/jbc.m510711200

Cited by 176 publications

(211 citation statements)

References 63 publications

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“…Alteration of the activities of these molecules can result in cell cycle progression, particularly during the G2/M phase. Pim-3 and Pim-1, but not Pim-2, bind to a consensus peptide substrate (AKRRRHPSGPPTA) with a strikingly high affinity, having K d value in the range of 40-60 nM (Bullock et al, 2005). Thus, it is likely that Pim-3 can phosphorylate these cell cycle regulators similarly as Pim-1.…”

Section: Discussionmentioning

confidence: 99%

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Wang

Nakamoto

et al. 2010

Oncogene

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Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN.

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Section: Discussionmentioning

confidence: 99%

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Wang

Nakamoto

et al. 2010

Oncogene

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“…To gain further insight into the mechanism of autophosphorylation, we overlaid the SnRK2.6 catalytic cleft with the structure of Pim-1, which, like the SnRK2s, is a member of the calmodulin-dependent protein kinase-related (CAMK) kinase family. The Pim-1 structure is in active conformation with a bound substrate peptide and the ATP analog AMP-PNP (42). As shown in Fig.…”

Section: Snrk26 Activation Loop Phosphate-acceptor Residues Are In Cmentioning

confidence: 99%

Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases

Soon

Zhou

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

155

163

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Abscisic acid (ABA) is an essential hormone that controls plant growth, development, and responses to abiotic stresses. Central for ABA signaling is the ABA-mediated autoactivation of three monomeric Snf1-related kinases (SnRK2.2, -2.3, and -2.6). In the absence of ABA, SnRK2s are kept in an inactive state by forming physical complexes with type 2C protein phosphatases (PP2Cs). Upon relief of this inhibition, SnRK2 kinases can autoactivate through unknown mechanisms. Here, we report the crystal structures of full-length Arabidopsis thaliana SnRK2.3 and SnRK2.6 at 1.9-and 2.3-Å resolution, respectively. The structures, in combination with biochemical studies, reveal a two-step mechanism of intramolecular kinase activation that resembles the intermolecular activation of cyclin-dependent kinases. First, release of inhibition by PP2C allows the SnRK2s to become partially active because of an intramolecular stabilization of the catalytic domain by a conserved helix in the kinase regulatory domain. This stabilization enables SnRK2s to gain full activity by activation loop autophosphorylation. Autophosphorylation is more efficient in SnRK2.6, which has higher stability than SnRK2.3 and has well-structured activation loop phosphate acceptor sites that are positioned next to the catalytic site. Together, these data provide a structural framework that links ABA-mediated release of PP2C inhibition to activation of SnRK2 kinases.

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“…22,88,115,116 These structural studies revealed a classic bilobal protein kinase domain architecture and apart from the unique beta hairpin insert located N-terminal to helix αC, all conserved secondary structure elements of typical protein kinases were present ( Figure 4). In protein kinases, the binding site for ATP is located in a deep cavity formed by the two kinase lobes and the connecting hinge region.…”

Section: Pim Kinases As Targets For Cancer Therapy Insights From the mentioning

confidence: 99%

“…7,19 Examination of the substrate sequence specificity of PIM1 revealed strong preference for peptides containing (K/R)3-X-S/T-X (X=neither basic nor large hydrophobic residue) 20 and positional peptide library screens identified a consensus sequence (ARKRRRHPS-GPPTA) that bound with low nM affinity to PIM kinases. 21,22 Mass-spectrometric analysis of Xenopus laevis PIM1 identified potential autophosphorylation sites including serine 190 and threonine 205 both conserved between species. 23 We have recently observed phosphorylation of PIM1 after heterologous expression in E.coli located on residue Ser261.…”

mentioning

confidence: 99%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

335

413

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The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

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Structure and Substrate Specificity of the Pim-1 Kinase

Cited by 176 publications

References 63 publications

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

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