Regulation of p27<i><sup>Kip1</sup></i>by mitogen-induced tyrosine phosphorylation

Jakel, Heidelinde; Peschel, Ines; Kunze, Clarissa; Weinl, Christina; Hengst, Ludger

doi:10.4161/cc.19957

Cited by 49 publications

(50 citation statements)

References 94 publications

(151 reference statements)

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“…8,16,20 On the other hand, as first exemplified by T187 phosphorylation of p27, 21 phosphorylations of Cip/Kip proteins, including by oncogenic tyrosine kinases, have also emerged as other potential mechanisms for CDK regulation. [22][23][24] Consistent with this idea, we have recently demonstrated that S130 phosphorylation of p21 inside the cyclin D-CDK4/6 complexes is catalyzed by other active CDK4/6 and CDK2 complexes and is required for the activating T172 phosphorylation of p21-bound CDK4 complexes. 15 Later at G1/S transition, S130 phosphorylation of p21 leads to its recognition by the SCF/Skp2 ubiquitin ligase complex and proteasomal degradation of cyclin/CDK-bound p21, hence contributing to CDK2 activation.…”

Section: Introductionsupporting

confidence: 58%

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

et al. 2014

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Section: Introductionsupporting

confidence: 58%

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

et al. 2014

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“…Tyrosine (Y) phosphorylation of p27 on residues Y74, Y88, and Y89 opens the cyclin D-cdk4-p27 ternary complex, rendering it able to phosphorylate substrates such as Rb (9)(10)(11)(12)(13)(14). Cyclin D-cdk4-p27 complexes isolated from cells in G 0 lack Y phosphorylation on p27 and are catalytically inactive, while complexes isolated from proliferating cells are Y phosphorylated and active.…”

mentioning

confidence: 99%

“…Independently of its ability to assemble cyclin D-cdk4 complexes, p27 acts as a bona fide "switch" turning cyclin D-cdk4 complexes on or off, which in turn modulates cell cycle entry or exit (8,9). Tyrosine (Y) phosphorylation of p27 on residues Y74, Y88, and Y89 opens the cyclin D-cdk4-p27 ternary complex, rendering it able to phosphorylate substrates such as Rb (9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Brk/Protein Tyrosine Kinase 6 Phosphorylates p27^KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4

Patel

Asbach

Shteyn

et al. 2015

Molecular and Cellular Biology

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Cyclin D and cyclin-dependent kinase 4 (cdk4) are overexpressed in a variety of tumors, but their levels are not accurate indicators of oncogenic activity because an accessory factor such as p27Kip1 is required to assemble this unstable dimer. Additionally, tyrosine (Y) phosphorylation of p27 (pY88) is required to activate cdk4, acting as an "on/off switch." We identified two SH3 recruitment domains within p27 that modulate pY88, thereby modulating cdk4 activity. Via an SH3-PXXP interaction screen, we identified Brk (breast tumor-related kinase) as a high-affinity p27 kinase. Modulation of Brk in breast cancer cells modulates pY88 and increases resistance to the cdk4 inhibitor PD 0332991. An alternatively spliced form of Brk (Alt Brk) which contains its SH3 domain blocks pY88 and acts as an endogenous cdk4 inhibitor, identifying a potentially targetable regulatory region within p27. Brk is overexpressed in 60% of breast carcinomas, suggesting that this facilitates cell cycle progression by modulating cdk4 through p27 Y phosphorylation. p27 has been considered a tumor suppressor, but our data strengthen the idea that it should also be considered an oncoprotein, responsible for cyclin D-cdk4 activity.C yclin D1-cyclin-dependent kinase 4 (cdk4) complexes promote the G 0 /G 1 -phase transition, and as such their activity is tightly regulated by a variety of mechanisms, including the transcription and translation of the mitogen sensor cyclin D1 and positive and negative regulatory phosphorylation of cdk4 (1, 2). The best-characterized substrate of cyclin D-cdk4 is the G 1 gatekeeper, retinoblastoma (Rb), and deregulation of cdk4 potentially accelerates Rb phosphorylation and cell cycle transitioning, promoting cancer development (3). Cyclin D1 and cdk4 are overexpressed in a variety of human cancers, and in mouse models, loss of either cdk4 or cyclin D1 prevents the development of certain oncogene-driven tumors, further evidence of their involvement (4-6). However, the levels of cyclin D or cdk4 in a tumor may not be reliable measures of activity, due to the fact that a third protein, an assembly factor such as p27Kip1 or p21Cip1, is required both for the stabilization and then the subsequent activation of this complex (1, 7).Independently of its ability to assemble cyclin D-cdk4 complexes, p27 acts as a bona fide "switch" turning cyclin D-cdk4 complexes on or off, which in turn modulates cell cycle entry or exit (8, 9). Tyrosine (Y) phosphorylation of p27 on residues Y74, Y88, and Y89 opens the cyclin D-cdk4-p27 ternary complex, rendering it able to phosphorylate substrates such as Rb (9-14). Cyclin D-cdk4-p27 complexes isolated from cells in G 0 lack Y phosphorylation on p27 and are catalytically inactive, while complexes isolated from proliferating cells are Y phosphorylated and active. Y88 and Y89 are part of the 3-to-10 helix, which has been shown to insert into the cdk ATP binding cleft (15). When not phosphorylated, residues Y88 and Y89 (Y88/Y89) sequester within this binding pocket and block cdk4 activity (p2...

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“…Cyclin D1 is transcribed following Ras-MAPK pathway activation, and the aberration of this molecular event underlies Ras-driven carcinogenesis (9,10). Phosphorylation of p27 kip1 (hereafter p27) on Ser-10, following Ras-MAPK pathway activation, impinges on its stability and subcellular localization, and has been proposed to play a central role in Ras-driven tumorigenesis (11,12).…”

mentioning

confidence: 99%

p27 ^kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

Fabris

Berton

Pellizzari

et al. 2015

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

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The cyclin-dependent kinase (CDK) inhibitor p27 kip1 is a critical regulator of the G1/S-phase transition of the cell cycle and also regulates microtubule (MT) stability. This latter function is exerted by modulating the activity of stathmin, an MT-destabilizing protein, and by direct binding to MTs. We recently demonstrated that increased proliferation in p27 kip1 -null mice is reverted by concomitant deletion of stathmin in p27 kip1 /stathmin double-KO mice, suggesting that a CDK-independent function of p27 kip1 contributes to the control of cell proliferation. Whether the regulation of MT stability by p27 kip1 impinges on signaling pathway activation and contributes to the decision to enter the cell cycle is largely unknown. Here, we report that faster cell cycle entry of p27 kip1 -null cells was impaired by the concomitant deletion of stathmin. Using gene expression profiling coupled with bioinformatic analyses, we show that p27 kip1 and stathmin conjunctly control activation of the MAPK pathway. From a molecular point of view, we observed that p27 kip1 , by controlling MT stability, impinges on H-Ras trafficking and ubiquitination levels, eventually restraining its full activation. Our study identifies a regulatory axis controlling the G1/S-phase transition, relying on the regulation of MT stability by p27 kip1 and finely controlling the spatiotemporal activation of the Ras-MAPK signaling pathway.

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Regulation of p27^Kip1by mitogen-induced tyrosine phosphorylation

Cited by 49 publications

References 94 publications

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

Brk/Protein Tyrosine Kinase 6 Phosphorylates p27^KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4

p27 ^kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

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Regulation of p27Kip1by mitogen-induced tyrosine phosphorylation

Cited by 49 publications

References 94 publications

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

Brk/Protein Tyrosine Kinase 6 Phosphorylates p27KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4

p27 kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

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Regulation of p27^Kip1by mitogen-induced tyrosine phosphorylation

Brk/Protein Tyrosine Kinase 6 Phosphorylates p27^KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4

p27 ^kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability