The protein phosphatase 6 catalytic subunit (Ppp6c) is indispensable for proper post-implantation embryogenesis

Ogoh, Honami; Tanuma, Nobuhiro; Matsui, Yasuhisa; Hayakawa, Natsuki; Inagaki, Asako; Sumiyoshi, Mami; Momoi, Yuki; Kishimoto, Ayako; Suzuki, Mai; Sasaki, Nozomi; Ohuchi, Tomohiro; Nomura, Miyuki; Teruya, Yuriko; Yasuda, Keiko; Watanabe, Toshio; Shima, Hiroshi

doi:10.1016/j.mod.2016.02.001

Cited by 28 publications

(22 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ppp6c homozygous null mutations are early embryonic lethal [45], necessitating use of conditional knockout approaches to study the role of PP6 in vivo . Ye et al [46] engineered mice that are homozygous for a LoxP-targeted allele on chromosome 2, which were crossed with Lck-Cre or CD4-Cre mice to drive selective deletion of the gene for PP6 catalytic subunit (PP6c) at early or intermediate stages of thymocyte development, respectively.…”

Section: Effects Of Ppp6c Knockout and Ppp6r1 (Saps1) Knockout On T Cmentioning

confidence: 99%

Functions of protein phosphatase-6 in NF-κB signaling and in lymphocytes

Ziembik

Bender

Larner

et al. 2017

Biochemical Society Transactions

View full text Add to dashboard Cite

Protein phosphatase-6 (PP6) is a member of the PPP family of Ser/Thr phosphatases involved in intracellular signaling. PP6 is conserved among all eukaryotes, and genetics in model organisms indicates it has non-redundant functions relative to other PPP phosphatases. PP6 functions in association with conserved SAPS subunits and, in vertebrate species, forms heterotrimers with Ankrd subunits. Multiple studies have demonstrated how PP6 exerts negative control at different steps of nuclear factor kappaB signaling. Expression of PP6 catalytic subunit and the PPP6R1 subunit is especially high in hematopoietic cells and lymphoid tissues. Recent efforts at conditionally knocking out genes for PP6c or PP6R1 (SAPS1) have revealed distinctive effects on development of and signaling in lymphocytes.

show abstract

Section: Effects Of Ppp6c Knockout and Ppp6r1 (Saps1) Knockout On T Cmentioning

confidence: 99%

Functions of protein phosphatase-6 in NF-κB signaling and in lymphocytes

Ziembik

Bender

Larner

et al. 2017

Biochemical Society Transactions

View full text Add to dashboard Cite

show abstract

“…Xenopus, mouse, human) three SAPS genes arose from whole-genome duplication and PP6 forms heterotrimers, where the SAPS and catalytic subunits associate with one of three ANKRD subunits composed of helical ankyrin repeats [6][7][8][9][10]. The loss of PP6 is embryonic lethal in mice [11,12] consistent with fundamental and essential cellular functions. The variety of PP6 functions (see review [3]) and dependence on individual SAPS support the idea that SAPS serve to determine substrate specificity.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase CK2 phosphorylation of SAPS3 subunit increases PP6 phosphatase activity with Aurora A kinase

Heo

Larner

Brautigan

2020

Biochemical Journal

View full text Add to dashboard Cite

Protein Ser/Thr phosphatase-6 (PP6) regulates pathways for activation of NF-kB, YAP1 and Aurora A kinase (AURKA). PP6 is a heterotrimer comprised of a catalytic subunit, one of three different SAPS subunits and one of three different ankyrin-repeat ANKRD subunits. Here, we show FLAG-PP6C expressed in cells preferentially binds endogenous SAPS3, and the complex is active with the chemical substrate DiFMUP. SAPS3 has multiple acidic sequence motifs recognized by protein kinase CK2 (CK2) and SAPS3 is phosphorylated by purified CK2, without affecting its associated PP6 phosphatase activity. However, HA3-SAPS3-PP6 phosphatase activity using pT288 AURKA as substrate is significantly increased by phosphorylation with CK2. The substitution of Ala in nine putative phosphorylation sites in SAPS3 was required to prevent CK2 activation of the phosphatase. Different CK2 chemical inhibitors equally increased phosphorylation of endogenous AURKA in living cells, consistent with reduction in PP6 activity. CRISPR/Cas9 deletion or siRNA knockdown of SAPS3 resulted in highly activated endogenous AURKA, and a high proportion of cells with abnormal nuclei. Activation of PP6 by CK2 can form a feedback loop with bistable changes in substrates.

show abstract

“…It has been reported that PPP6C homozygous null mutations are early embryonic lethal in mice (Ogoh et al, 2016 ). To investigate the functions of PPP6C in vivo , we crossed the Ppp6c f / f mice with Vav1-Cre mice to obtain Ppp6c hematopoietic-specific knockout strain ( Ppp6c f / f : Vav1-Cre ).…”

Section: Resultsmentioning

confidence: 99%

Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

Shu

2020

Protein Cell

View full text Add to dashboard Cite

The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosolic DNA derived from microbial pathogens or mis-located cellular DNA. Upon DNA binding, cGAS utilizes GTP and ATP as substrates to synthesize cGAMP, leading to MITA-mediated innate immune response. In this study, we identified the phosphatase PPP6C as a negative regulator of cGAS-mediated innate immune response. PPP6C is constitutively associated with cGAS in un-stimulated cells. DNA virus infection causes rapid disassociation of PPP6C from cGAS, resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket. Mutation of this serine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection. In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity. PPP6C-deficiency promotes innate immune response to DNA virus in various cells. Our findings suggest that PPP6C-mediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response, which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.

show abstract

The protein phosphatase 6 catalytic subunit (Ppp6c) is indispensable for proper post-implantation embryogenesis

Cited by 28 publications

References 48 publications

Functions of protein phosphatase-6 in NF-κB signaling and in lymphocytes

Functions of protein phosphatase-6 in NF-κB signaling and in lymphocytes

Protein kinase CK2 phosphorylation of SAPS3 subunit increases PP6 phosphatase activity with Aurora A kinase

Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

Contact Info

Product

Resources

About