Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

Bitomsky, Nadja; Conrad, Elisa; Moritz, Christian P.; Polonio-Vallon, Tilman; Sombroek, Dirk; Schultheiss, Kathrin; Glas, Carolina; Greiner, Vera; Herbel, Christoph; Mantovani, Fiamma; Sal, Giannino Del; Peri, Francesca; Hofmann, Thomas G.

doi:10.1073/pnas.1310001110

Cited by 44 publications

(59 citation statements)

References 40 publications

(60 reference statements)

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“…His-HIPK2 was found to be strongly auto-phosphorylated ( Fig. 2A), which is a prerequisite for its proper activity (20). Interestingly, the fulllength AIRE protein (and truncated AIRE products) was clearly phosphorylated by HIPK2.…”

Section: Hipk2 Phosphorylates Aire In Vitro and Represses Its Transcrmentioning

confidence: 95%

“…In vitro phosphorylation of bacterially expressed and purified GST-AIRE was performed using 6xHis-HIPK2 purified from E. coli essentially as described previously (20). In brief, 1.5 mg purified GST-AIRE was incubated with 100 ng 6xHis-HIPK2 protein in kinase reaction buffer containing g-[…”

Section: In Vitro Phosphorylation Assaymentioning

confidence: 99%

“…In vitro phosphorylation reactions were analyzed by SDS-PAGE and autoradiography as described previously (20).…”

mentioning

confidence: 99%

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Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

Rattay

Claude

Rezavandy

et al. 2015

The Journal of Immunology

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Promiscuous expression of a plethora of tissue-restricted Ags (TRAs) by medullary thymic epithelial cells (mTECs) plays an essential role in T cell tolerance. Although the cellular mechanisms by which promiscuous gene expression (pGE) imposes T cell tolerance have been well characterized, the underlying molecular mechanisms remain poorly understood. The autoimmune regulator (AIRE) is to date the only validated molecule known to regulate pGE. AIRE is part of higher-order multiprotein complexes, which promote transcription, elongation, and splicing of a wide range of target genes. How AIRE and its partners mediate these various effects at the molecular level is still largely unclear. Using a yeast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain-interacting protein kinase 2 (HIPK2) as a novel partner. HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human mTECs in situ. Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of AIRE in a kinase-dependent manner. To evaluate the role of Hipk2 in modulating the function of AIRE in vivo, we compared whole-genome gene signatures of purified mTEC subsets from TEC-specific Hipk2 knockout mice with control mice and identified a small set of differentially expressed genes. Unexpectedly, most differentially expressed genes were confined to the CD80lo mTEC subset and preferentially included AIRE-independent TRAs. Thus, although it modulates gene expression in mTECs and in addition affects the size of the medullary compartment, TEC-specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo.

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Section: Hipk2 Phosphorylates Aire In Vitro and Represses Its Transcrmentioning

confidence: 95%

Section: In Vitro Phosphorylation Assaymentioning

confidence: 99%

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Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

Rattay

Claude

Rezavandy

et al. 2015

The Journal of Immunology

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“…For example, isomerisation mediates the spatiotemporal control of fundamental processes including cell cycle progression, cell proliferation and cell death [1][2][3][4]. In recent years, mounting evidence implicates deregulated isomerase activity in a range of age-related pathologies including neurodegeneration, cardiovascular disease and cancer [5].…”

Section: Introductionmentioning

confidence: 99%

Cyclophilin function in Cancer; lessons from virus replication

Lavin¹

2015

CMP

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Cyclophilins belong to a group of proteins that possess peptidyl prolyl isomerase activity and catalyse the cis-trans conversion of proline peptide bonds. Cyclophilin members play important roles in protein folding and as molecular chaperones, in addition to a wellestablished role as host factors required for completion of the virus life cycle. Members of the cyclophilin family are overexpressed in a range of human malignancies including hepatocellular cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, colorectal cancer and glioblastoma multiforme, however, their precise role in tumourigenesis remains unclear. In recent years, mounting evidence supports a role for prolyl isomerisation during mammalian cell division; a process with striking similarity to plasma membrane remodelling during virus replication. Here we will summarise our current understanding of the role of cyclophilins in cancer. We will review the function of cyclophilins during mammalian cell division and during HIV-1 infection, and highlight common processes involving members of the ESCRT and Rab GTPase families. IntroductionThe interconversion of protein backbone between cis and trans, catalysed by peptidyl prolyl isomerases (PPIases), is an important event that alters protein structure and activity and regulates a wide spectrum of cellular functions in normal physiological processes. For example, isomerisation mediates the spatiotemporal control of fundamental processes including cell cycle progression, cell proliferation and cell death [1][2][3][4]. In recent years, mounting evidence implicates deregulated isomerase activity in a range of age-related pathologies including neurodegeneration, cardiovascular disease and cancer [5]. As a result, isomerases have gained significant interest as therapeutic targets in the treatment of these diseases.

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“…Moreover, phosphorylation at Thr880/Ser882 serves as a binding signal for the cis/trans isomerase Pin1, which couples HIPK2 activation to its stabilization by changing HIPK2 conformation. 15 After lethal DNA damage, HIPK2 site-specifically phosphorylates the tumor suppressor protein p53 at Serine residue 46 and thereby activates the expression of pro-apoptotic p53 target genes. 16,17 The growth-suppressive and apoptotic activity of HIPK2 has been tightly linked to its localization to the cell nucleus, in particular to its association with promyelocytic leukemia (PML) nuclear bodies (NBs).…”

Section: Introductionmentioning

confidence: 99%