Successive Phosphorylation of p27KIP1 Protein at Serine-10 and C Terminus Crucially Controls Its Potency to Inactivate Cdk2

Mohanty, Atish; Kan, Qiuming; Srivastava, Saumya; Uranbileg, Baasanjav; Arakawa-Takeuchi, Shiho; Fujita, Naoya; Okayama, Hiroto

doi:10.1074/jbc.m112.346254

Cited by 8 publications

(12 citation statements)

References 27 publications

(40 reference statements)

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“…In this mechanism, Cdc6, the AAA+ ATPase previously identified as the assembly factor for the formation of preRC on ORC-bound chromosomal replication origins, removes the bound p27 Kip1 from p27 Kip1 -bound inactive Cdk2-Cyclin A/E complexes through its ATP-dependent remodeling function after anchorage-activated ROCK phosphorylates the C-terminal threonine of the bound p27 Kip1 . 32,33) This regulatory cascade corresponds to the pattern of Cascade I-6 in Fig. 1, which requires three cascade signals originating from one stimulus for invoking one particular response.…”

Section: Discussionmentioning

confidence: 99%

General strategy for understanding intracellular molecular interaction cascades that elicit stimulus-invoked biological processes

Okayama

2016

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Recent advances in biology have been driven by chemical analyses of the substances that form living organisms. Such analyses are extremely powerful as way of learning about the static properties of molecular species, but relatively powerless for understanding their dynamic behaviors even though this dynamism is essential for organisms to perform various biological processes that perpetuate their lives. Thus, attempts to identify individual species and molecular interaction cascades that drive specific responses to external stimuli or environmental changes often fail. Here I propose a general strategy to address this problem. The strategy comprises two key elements: functional manipulation of a given protein molecule coupled with close monitoring of its biological effect, and construction of a knowledge base tailored for conjecture-driven experimentation. The original idea for this strategy co-evolved with and greatly helped a series of studies we recently performed to discover critical signal cascades and cellular components that regulate the cell cycle transition from G1 to S phase.

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Section: Discussionmentioning

confidence: 99%

General strategy for understanding intracellular molecular interaction cascades that elicit stimulus-invoked biological processes

Okayama

2016

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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“…Thus, while S10 phosphorylation of p27 is a positive regulatory modification, T187 and T198 phosphorylation are both negative regulatory modifications. In addition, S10 phosphorylation is a known prerequisite for subsequent phosphorylation on T187 and T198 35,44–46 . We found that levels of S10 phosphorylation mirrored that of total p27 (Fig 4a,c), indicating that the PIM inhibition did not interfere with S10 phosphorylation.…”

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confidence: 99%

PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression

Horiuchi

Camarda

Zhou

et al. 2016

Nat Med

148

142

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Triple-negative breast cancer (TNBC), which lacks the expression of the estrogen, progesterone, and HER2 receptors, represents the breast cancer subtype with the poorest outcome1. No targeted therapy is available against this subtype due to lack of validated molecular targets. We previously reported that MYC signaling is disproportionally elevated in triple-negative (TN) tumors compared to receptor-positive (RP) tumors2. MYC is an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes3. Direct inhibition of oncogenic MYC transcriptional activity has remained challenging4,5. The present study conducted an shRNA screen against all kinases to uncover novel MYC-dependent synthetic lethal combinations, and identified PIM1, a non-essential kinase. Here we demonstrate that PIM1 expression was elevated in TN tumors and was associated with poor prognosis in patients with hormone and HER2 receptor-negative tumors. Small molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic breast cancer models by inhibiting oncogenic transcriptional activity of MYC while simultaneously restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that exhibit elevated MYC expression.

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“…Moreover, p27Kip1 interacts with several CDK/cyclin unrelated proteins and, in this way, it controls numerous molecular events, including DNA duplication, gene transcription, cell movement and substrate interaction, apoptosis and differentiation. [5][6][7][8][9][10][11][12][13][14][15] The variety of p27Kip1 interactors is remarkably increased by the lack of p27Kip1 stable tertiary structure. [16][17][18] This feature, that allows p27Kip1 to be an archetypal member of the so-called "intrinsically unstructured proteins" (IUP) family, enhances p27Kip1 "adaptability."…”

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confidence: 99%

“…However, different roles for T157/T198 phosphorylation have been proposed including the control of cell motility, nuclear entry of active CDK4 (6) and DNA duplication. 5,11,12 Several putative kinases have been identified as responsible for T157/T198 phosphorylation, namely AMPK, p90RSK, glucocorticoid inducible kinase (SGK), ROCK and Pim. 5,[10][11][12][31][32][33][34] Recently, it was shown that p27Kip1-dependent restrain to S phase entry is relieved by its tyrosine phosphorylation on different residues (Y88, Y89 and Y74).…”

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confidence: 99%

“…5,11,12 Several putative kinases have been identified as responsible for T157/T198 phosphorylation, namely AMPK, p90RSK, glucocorticoid inducible kinase (SGK), ROCK and Pim. 5,[10][11][12][31][32][33][34] Recently, it was shown that p27Kip1-dependent restrain to S phase entry is relieved by its tyrosine phosphorylation on different residues (Y88, Y89 and Y74). [35][36][37][38][39] Particularly, Y88 phosphorylation should eject a p27Kip1 inhibitory segment from the active site of CDK2, thus restoring the kinase activity.…”

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confidence: 99%

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p27Kip1 serine 10 phosphorylation determines its metabolism and interaction with cyclin-dependent kinases

Bencivenga¹,

Tramontano²,

Borgia³

et al. 2014

Cell Cycle

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p27Kip1 is a critical modulator of cell proliferation by controlling assembly, localization and activity of cyclin-dependent kinase (CDK). p27Kip1 also plays important roles in malignant transformation, modulating cell movement and interaction with the extracellular matrix. A critical p27Kip1 feature is the lack of a stable tertiary structure that enhances its "adaptability" to different interactors and explains the heterogeneity of its function. The absence of a well-defined folding underlines the importance of p27Kip1 post-translational modifications that might highly impact the protein functions. Here, we characterize the metabolism and CDK interaction of phosphoserine10-p27Kip1 (pS10- p27Kip1), the major phosphoisoform of p27Kip1. By an experimental strategy based on specific immunoprecipitation and bidimensional electrophoresis, we established that pS10-p27Kip1 is mainly bound to cyclin E/CDK2 rather than to cyclin A/CDK2. pS10- p27Kip1 is more stable than non-modified p27Kip1, since it is not (or scarcely) phosphorylated on T187, the post-translational modification required for p27Kip1 removal in the nucleus. pS10-p27Kip1 does not bind CDK1. The lack of this interaction might represent a mechanism for facilitating CDK1 activation and allowing mitosis completion. In conclusion, we suggest that nuclear p27Kip1 follows 2 almost independent pathways operating at different rates. One pathway involves threonine-187 and tyrosine phosphorylations and drives the protein toward its Skp2-dependent removal. The other involves serine-10 phosphorylation and results in the elongation of p27Kip1 half-life and specific CDK interactions. Thus, pS10-p27Kip1, due to its stability, might be thought as a major responsible for the p27Kip1-dependent arrest of cells in G1/G0 phase.

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Successive Phosphorylation of p27KIP1 Protein at Serine-10 and C Terminus Crucially Controls Its Potency to Inactivate Cdk2

Cited by 8 publications

References 27 publications

General strategy for understanding intracellular molecular interaction cascades that elicit stimulus-invoked biological processes

General strategy for understanding intracellular molecular interaction cascades that elicit stimulus-invoked biological processes

PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression

p27Kip1 serine 10 phosphorylation determines its metabolism and interaction with cyclin-dependent kinases

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