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The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation: PLK1 PRM

ABSTRACT: The aim of these experiments was to quantify PLK1 tyrosine phosphosites with respect to EYA4 and EYA1. PRM was performed on immunopurified PLK1. This was part of a larger project to characterize the effects of EYA4 mediated dephosphorylation on PLK1 functions.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Christopher Nelson

LAB HEAD: Hilda Amelia

PROVIDER: PXD037064 | Pride | 2024-02-26

REPOSITORIES: Pride

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			Action	DRS
	04032020_Benz_A.msf	Msf
	04032020_Benz_A.raw	Raw
	04032020_Benz_B.msf	Msf
	04032020_Benz_B.raw	Raw
	04032020_Benz_C.msf	Msf

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Publications

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation.

Nelson Christopher B CB Rogers Samuel S Roychoudhury Kaushik K Tan Yaw Sing YS Atkinson Caroline J CJ Sobinoff Alexander P AP Tomlinson Christopher G CG Hsu Anton A Lu Robert R Dray Eloise E Haber Michelle M Fletcher Jamie I JI Cesare Anthony J AJ Hegde Rashmi S RS Pickett Hilda A HA

Nature communications 20240215 1

The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 locali ...[more]

PMID: 38360978

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Mass spectrometry analysis of in vitro PLK1 phosphorylation

Project description:Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

2024-11-01 | PXD053933 | Pride

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation: siEYA4 pY IP-MS

Project description:The Eyes Absent family of proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour promoting across a range of cancer types. To date, the molecular targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as a direct interactor and phosphatase substrate of both EYA4 and EYA1, with pY445 on PLK1 being the primary target site. EYA-mediated dephosphorylation of PLK1 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and the PLK1-activating proteins BORA and CEP192. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a novel phosphotyrosine signalling network governing PLK1 and mitosis. This work provides a mechanism of cell killing for EYA phosphatase inhibitors with important therapeutic implications.

2024-02-26 | PXD036430 | Pride

PRC1 phosphorylation by CDK1 and PLK1

Project description:This work study the effects of PRC1 phosphorylation by CDK1 and PLK1.

2024-11-01 | PXD055933 | Pride

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation: EYA4 BioID

Project description:The aim of this project was to identify the EYA4 interactome. This was part of a larger research goal of identifying EYA4 phosphatase substrates and the cell biological consequences of their dephosphorylation.

2024-02-26 | PXD036405 | Pride

PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to mTOR-targeted Therapy.

Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K

2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress

PLK1 phosphorylation of Epstein-Barr virus nuclear antigen 2

Project description:The Epstein-Barr virus nuclear antigen 2 (EBNA2) initiates and maintains the proliferation of infected B cells. In search of additional cellular strategies, that control EBNA2 function, we have performed a label-free mass spectrometry-based quantification of cellular proteins in EBNA2 immuno-precipitates and found polo-like kinase 1 (PLK1) to be bound to EBNA2. EBNA2/PLK1 complex formation is strongly enforced by EBNA2 S379 phosphorylation catalyzed by the mitotic CYCLIN B/CDK1 complex.

2021-08-22 | PXD022970 | Pride

Phosphorylation of Rif1 by Plk1

2021-08-26 | PXD022410 | Pride

Protein recruitment on chromatin in the presence or absence of Plk1

2021-08-25 | PXD022572 | Pride

Identification of Plk1 interacting proteins by XChIP-MS

Project description:Polo-like kinase 1 (Plk1) is an important protein kinase for checkpoint recovery and adaptation in response to DNA damage and replication stress. However, although Plk1 is present in S phase, little is known about its localization and function during unperturbed DNA replication. Using Xenopus laevis egg extracts, mimicking early embryonic replication, we developed a Plk1 chromatin immunoprecipitation approach followed by a proteomic shotgun analysis (XChIP-MS) to identify Plk1 interactions with chromatin and with specific nuclear proteins. We purified and cross-linked nuclei after pre-RC assembly before the start of DNA replication, or later during DNA replication. The DNA was fractionated by sonication and immunoprecipited using anti Plk1 or control antibodies then proteins were analyzed by nanoLC/MS/MS.

2021-08-25 | PXD022440 | Pride

Expression profile in Plk1(+/-) aortas

Project description:Transcriptional profiling of mouse aortas comparing control wild-type animals with aortas from three different Plk1(+/-) mice. Goal was to determine the effects of Plk1 haploinsufficiency in aorta expression profiles.

2017-07-01 | GSE85199 | GEO

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