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A novel YDDX linear motif mediates docking of the IKK kinase to substrates: structural and functional insights

ABSTRACT: The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors. The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Juri Rappsilber

PROVIDER: PXD037534 | JPOST Repository | Thu May 09 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	B210905_02_Lumos_FO_CO_150_IKKbetaPlusPeptideK21_BS3_monomer_rep2.raw	Raw
	B210905_03_Lumos_FO_CO_150_IKKbetaPlusPeptideK21_BS3_monomer_rep3.raw	Raw
	B210905_05_Lumos_FO_CO_150_IKKbetaPlusPeptideK21_EDC_monomer_rep2.raw	Raw
	B220404_05_Lumos_FO_CO_120_Zanier_SDA_monomer_upper_rep1.raw	Raw
	IKKbPlusPeptide_BS3_monomer.mzid	Mzid

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Project description:Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 in the N-terminal transactivation domain. In this study, the role of this phosphorylation site was investigated by characterizing the phosphorylation site mutant in the context of full length and truncated AR lacking the ligand-binding domain. The Y267F mutant showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. Expression of AR responsive genes in cells expressing truncated AR wt and AR-Y267F mutant under androgen deprived conditions was assessed by microarray gene expression analysis. The AR pathway score was increased in cells expressing truncated AR wt and decreased in cells expressing truncated AR-Y267F. These results support the concept that phosphorylation of Tyr-267 is required for AR nuclear translocation and recruitment and DNA binding and transcription of AR responsive genes. Gene expression profiling was performed using RNA samples from LNCaP cells expressing truncated AR-wt and truncated AR-Y267F growing in androgen deprived conditions. The RNA sample from vector control cells were used as reference sample. Two biological replicates were used per each cell line.

Dataset Information

A novel YDDX linear motif mediates docking of the IKK kinase to substrates: structural and functional insights

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