Editors' ChoiceBiochemistry

New connections: HIPK2 becomes crystal clear

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Science Signaling  30 Jul 2019:
Vol. 12, Issue 592, eaay8936
DOI: 10.1126/scisignal.aay8936

Solving the crystal structure of HIPK2 may lead to therapeutic targeting of this versatile kinase.

Homeodomain-interacting protein kinase 2 (HIPK2) is a member of a family of dual-specificity serine-threonine and tyrosine kinases belonging to the CMGC superfamily. HIPKs function as transcriptional regulators and corepressors of homeodomain transcription factors. HIPK2 phosphorylates p53 as part of the DNA damage response, enabling p53-dependent gene expression and apoptosis. However, HIPK2 is also implicated in other cellular responses. In the Archives, Cao et al. showed in mice that HIPK2 was required for resistance to viral infection and for the production of type I interferon (IFN). This antiviral response required nuclear translocation of the kinase and the cleavage of its autoinhibitory domain. As Best and Ponia discuss in the Archives, this work suggests that targeting HIPK2 therapeutically might dampen type I IFN production in autoimmune diseases. HIPK2 is also overexpressed in various cancers and is implicated in chronic fibrosis. Now, Agnew et al. have solved the crystal structure of the kinase domain of HIPK2 bound to the casein kinase 2α (CK2α) inhibitor CX-4945, which is in clinical trials for several cancers. The HIPK2 kinase domain, which was crystallized in the active conformation, was stabilized through active loop phosphorylation. The authors further characterized the manner in which CX-4945 engaged the active site of HIPK2, as well as structural similarities and differences between HIPK2 and related dual-specificity kinases of the DYRK family. Solving the structure of HIPK2 should facilitate the development of specific inhibitors that might be used for the treatment of cancers, fibrosis, and potentially autoimmunity.

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