Complex regulation of CREB-binding protein by homeodomain-interacting protein kinase 2

Abstract

CREB-binding protein (CBP) and p300 are transcriptional coactivators involved in numerous biological processes that affect cell growth, transformation, differentiation, and development. In this study, we provide evidence of the involvement of homeodomain-interacting protein kinase 2 (HIPK2) in the regulation of CBP activity. We show that HIPK2 interacts with and phosphorylates several regions of CBP. We demonstrate that serines 2361, 2363, 2371, 2376, and 2381 are responsible for the HIPK2-induced mobility shift of CBP C-terminal activation domain. Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CBP.However, our data suggest that HIPK2 activates CBP mainly by counteracting the repressive action of cell cycle regulatory domain 1 (CRD1), located between amino acids 977 and 1076, independently of CBP phosphorylation. Our findings thus highlight a complex regulation of CBP activity by HIPK2, which might be relevant for the control of specific sets of target genes involved in cellular proliferation, differentiation and apoptosis.

Arsenic-Induced Activation of the Homeodomain-Interacting Protein Kinase 2 (HIPK2) to cAMP-Response Element Binding Protein (CREB) Axis

“…Given the fact that CREB dimerizes with other b-zip family members including ATF1 [58], both of which are subject to phosphorylation at multiple Ser/Thr sites by the canonical and stress signaling pathways leading to preferential recruitment of a specific set of coactivators including CBP/p300 and TORC2 (transducer of regulated CREB) [29,59]. In addition, HIPK2 phosphorylates p300 [60] and CBP [61] that activate p300 and CBP transcriptional coactivator functions. Although we did not observe enhanced interaction between CREB S271E and CBP in transfected cells, activation of HIPK2 by arsenic and DNA stress may not only facilitate CREB-TAF4 interaction but also activate p300/CBP through multiple sites of phosphorylation as reported [60,61].…”

“…In addition, HIPK2 phosphorylates p300 [60] and CBP [61] that activate p300 and CBP transcriptional coactivator functions. Although we did not observe enhanced interaction between CREB S271E and CBP in transfected cells, activation of HIPK2 by arsenic and DNA stress may not only facilitate CREB-TAF4 interaction but also activate p300/CBP through multiple sites of phosphorylation as reported [60,61]. …”

Increasing temperature-driven changes in life history traits and gene expression of an Antarctic tardigrade species

“…Among the 44 DEGs that were downregulated with the increase in temperature, there are genes related to the protein turnover ( cathepsin B and UBA domain-like superfamily; Förster et al, 2012 ), a gene ( Multidrug resistance-associated protein 1 ) involved in dauer larva regulation of the nematode Caenorhabditis elegans ( Yabe et al, 2005 ), and two genes (CREB-binding protein and Homeodomain-interacting protein kinase 2 ) relevant for the control of cellular proliferation, differentiation and apoptosis ( Kovács et al, 2015 ). The loss of function of a Homeodomain-interacting protein kinase (HPK) shortens lifespan and hastens tissue aging in C. elegans ( Berber et al, 2016 ).…”

Chromatin Targeting of HIPK2 Leads to Acetylation-Dependent Chromatin Decondensation

“…The association of HIPK2 with HATs increases their coactivator function, which can involve an elevated HAT activity, as shown by in vitro experiments for the p300 protein ( Aikawa et al, 2006 ). In addition, HIPK2 can activate CBP by counteracting the repressive action of cell cycle regulatory domain 1 ( Kovacs et al, 2015 ). Also other members of the HIPK family can associate with p300.…”