The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling

Cen, Bo; Xiong, Ying; Song, Jin H.; Mahajan, Sandeep; DuPont, Rachel; McEachern, Kristen; DeAngelo, Daniel J.; Cortes, Jorge; Minden, Mark D.; Ebens, Allen; Mims, Alice S.; LaRue, Amanda C.; Kraft, Andrew S.

doi:10.1128/mcb.00147-14

Cited by 53 publications

(65 citation statements)

References 28 publications

(50 reference statements)

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“…Consistent with a recent study (27), we find that eIF4B phosphorylation at Ser406 is required for the interaction between eIF4B and the eIF3 translation initiation complex. Those observations suggest a model in which eIF4B phosphorylation promotes the recruitment of ribosomes to mRNA and, consequently, protein synthesis.…”

Section: Discussionsupporting

confidence: 93%

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

Wang

Begley

et al. 2016

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

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The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MELKeIF4B signaling axis regulates protein synthesis during mitosis. Specifically, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in cancer cell survival during cell division, depends on the function of MELK-elF4B. Inactivation of MELK or eIF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of cancer cells. Our study thus defines a MELK-eIF4B signaling axis that regulates protein synthesis during mitosis, and consequently influences cancer cell survival.aternal and embryonic leucine zipper kinase (MELK) is a serine/threonine kinase with potential roles in mitosis. Similar to other established mitotic factors, such as Aurora kinases and cyclin B1, MELK demonstrates increased protein abundance during mitosis and is degraded when cells progress into G1 phase (1, 2). Our recent study proposed an essential role of MELK in the mitotic progression of specific cancer cell types, with MELK knockdown resulting in multiple mitotic defects, including G2/M arrest and mitotic cell death (2). Despite these advances, there is a lack of mechanistic understanding of the role of MELK during cell division. An immediate question is the identity of the MELK substrates that mediate its role in mitosis, such as promoting mitotic cell survival.Myeloid cell leukemia 1 (MCL1) is an important negative regulator of apoptosis. Uniquely among the Bcl-2 family, it is turned over rapidly by ubiquitin-mediated proteolysis and must be continuously resupplied by translation (3, 4). Protein abundance of MCL1 decreases during prolonged mitotic arrest induced by antimicrotubule drugs, rendering arrested cells highly sensitive to inhibitors of other Bcl-2 family members (5). We thus speculate that synthesis of MCL1 is important for cell survival during normal and drug-arrested mitosis and, conversely, that a drug that decreases MCL1 synthesis during mitosis might have anticancer potential.The rate of protein synthesis and other basic biological processes, such as DNA or RNA biogenesis, fluctuates throughout the cell cycle. Overall protein synthesis significantly decreases when cells enter mitosis (6, 7), consistent with the notion that macromolecule synthesis predominantly occurs in interphase before the segregation of cellular mass in mitosis.A recent study based on ribosome profiling identified a set of genes that are translationally repressed in mitosis, and proposed that suppressed protein synthesis migh...

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Section: Discussionsupporting

confidence: 93%

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

Wang

Begley

et al. 2016

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

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“…2A–C). This induction was blocked by the addition to the media of either of two pan-PIM1 inhibitors, AZD1208 (AstraZeneca) (26) or GNE-652 (Genentech) (27)(Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

“…Because we had previously established that PIM1 expression in PCa epithelial cells can control the levels of receptor tyrosine kinases (27, 30), we studied whether elevated PIM1 levels also mediated changes in tyrosine receptors (RTKs) in prostate fibroblasts. BHPrS1/PIM1 cells with and without PIM1 induction by Dox were examined by phosphoreceptor tyrosine kinases arrays (R&D Systems) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S3C). The PIM protein kinases have been shown to regulate translation through modulating the phosphorylation of PRAS40, TSC-2, 4E-BP1, and eIF4B (13, 27, 33, 34), leading to stimulation of mTOR activity and enhancing 5’Cap induced translation. Western blot analysis of extracts of PIM1 overexpressing BHPrS1 cells compared to control cells not only demonstrated an increase in COL1A1 and PDGFRβ protein levels, but also showed increased phosphorylation of the PIM1 target eIF4B (S406) (27), a protein that regulates the mRNA helicase eIF4A that is needed for 5’ Cap dependent translation (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Regulation of prostate stromal fibroblasts by the PIM1 protein kinase

Zemskova

Song

Cen

et al. 2015

Cellular Signalling

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The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 overexpressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5’Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFRβ mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs.

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“…However, mTORC1-p70S6K inhibition did not affect the basal or PMA-induced levels of eIF4B phosphorylation in LN-18 cells. Varying sensitivities to rapamycin were observed for eIF4B phosphorylation in different cell types [27,56,57], and thus unknown contributions by p70S6K may explain the discrepancies in the reported effects of BI-D1870 on eIF4B phosphorylation (Supplementary Table S3). In contrast to BI-D1870, the effect of SL0101 on eIF4B phosphorylation has not previously been reported.…”

Section: Discussionmentioning

confidence: 99%