Protein Phosphatase 4 Is a Positive Regulator of Hematopoietic Progenitor Kinase 1

Zhou, Guisheng; Boomer, Jonathan S.; Tan, Tse‐Hua

doi:10.1074/jbc.m410317200

Cited by 42 publications

(25 citation statements)

References 79 publications

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“…In vitro PP5 can dephosphorylate Thr845, an activation-associated site on ASK1. These findings suggest that PP5 functions to inactivate ASK1 and perhaps other MAP3Ks (Zhou et al, 2004).…”

Section: Phosphatasesmentioning

confidence: 88%

Differential regulation and properties of MAPKs

2007

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Mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs including embryogenesis, proliferation, differentiation and apoptosis based on cues derived from the cell surface and the metabolic state and environment of the cell. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK(1-3)) and p38(a, b, c and d) families. ERK3, ERK5 and ERK7 are other MAPKs that have distinct regulation and functions. MAPK cascades consist of a core of three protein kinases. Despite the apparently simple architecture of this pathway, these enzymes are capable of responding to a bewildering number of stimuli to produce exquisitely specific cellular outcomes. These responses depend on the kinetics of their activation and inactivation, the subcellular localization of the kinases, the complexes in which they act, and the availability of substrates. Fine-tuning of cascade activity can occur through modulatory inputs to cascade component from the primary kinases to the scaffolding accessory proteins. Here, we describe some of the properties of the three major MAPK pathways and discuss how these properties govern pathway regulation and activity.

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“…In vitro PP5 can dephosphorylate Thr845, an activation-associated site on ASK1. These findings suggest that PP5 functions to inactivate ASK1 and perhaps other MAP3Ks (Zhou et al, 2004).…”

Section: Phosphatasesmentioning

confidence: 88%

Differential regulation and properties of MAPKs

2007

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“…In addition, the characterization of PP4-interacting proteins during pre-TCR or TCR signaling may further elucidate the functional roles of PP4 in T-cell development, apoptosis, and activation. Specifically, our previous studies have demonstrated that PP4 interacts with, dephosphorylates, and activates HPK1 (30), an upstream kinase known to regulate T-cell activation and apoptosis (1,20). Moreover, PP4 associates with, dephosphorylates, and inhibits histone deacetylase 3 (29), which was originally cloned from phytohemagglutinin-activated T cells and whose mRNA is upregulated in peripheral blood mononuclear cells cultured with anti-CD3 antibody (3).…”

Section: Discussionmentioning

confidence: 99%

“…In yeast, Pph3, but not Pph22, dephosphorylates ␥H2AX, whose posttranslational modification is an early hallmark following a double-strand break (15). PP4 interacts with and regulates HPK1, a mitogen-activated protein kinase upstream regulator, in a T-cell receptor (TCR)-dependent manner (30), indicating that PP4 may be a novel serine/threonine phosphatase involved in T-cell signaling. By conditional inactivation of PP4 in the T-cell lineage, aberrant thymocyte development, including double-negative 3 stage (DN3) cell arrest and decreased positive selection, was detected.…”

mentioning

confidence: 99%

Conditional Knockout Mice Reveal an Essential Role of Protein Phosphatase 4 in Thymocyte Development and Pre-T-Cell Receptor Signaling

Shui

Tan

2007

Molecular and Cellular Biology

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Okadaic acid-sensitive serine/threonine phosphatases have been shown to regulate interleukin-2 transcription and T-cell activation. Okadaic acid inhibits protein phosphatase 4 (PP4), a novel PP2A-related serine/ threonine phosphatase, at a 50% inhibitory concentration (IC 50 ) comparable to that for PP2A. This raises the possibility that some cellular functions of PP2A, determined in T cells by using okadaic acid, may in fact be those of PP4. To investigate the in vivo roles of PP4 in T cells, we generated conventional and T-cell-specific PP4 conditional knockout mice. We found that the ablation of PP4 led to the embryonic lethality of mice. PP4 gene deletion in the T-cell lineage resulted in aberrant thymocyte development, including T-cell arrest at the double-negative 3 stage (CD4 ؊ CD8 ؊ CD25 ؉ CD44 ؊ ), abnormal thymocyte maturation, and lower efficacy of positive selection. PP4-deficient thymocytes showed decreased proliferation and enhanced apoptosis in vivo. Analysis of pre-T-cell receptor (pre-TCR) signaling further revealed impaired calcium flux and phospholipase C-␥1-extracellular signal-regulated kinase activation in the absence of PP4. Anti-CD3 injection in PP4-deficient mice led to enhanced thymocyte apoptosis, accompanied by increased proapoptotic Bim but decreased antiapoptotic Bcl-xL protein levels. In the periphery, antigen-specific T-cell proliferation and T-cell-mediated immune responses in PP4-deficient mice were dramatically compromised. Thus, our results indicate that PP4 is essential for thymocyte development and pre-TCR signaling.

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“…In doing so, it has been suggested that PP4 presumably activates NF-B and facilitates TNF␣-induced activation of JNK kinase (Zhou et al 2002;Mihindukulasuriya et al 2004;Yeh et al 2004;Zhou et al 2004). Since HDAC3 is a regulator of NF-B and of the JNK pathway Zhang et al 2002;Weiss et al 2003), it will be important to elucidate the association of HDAC3 dephosphorylation by PP4 with these signaling pathways in future studies.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4

Zhang¹,

Ozawa²,

Lee³

et al. 2005

Genes Dev.

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199

207

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Histone deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of histones and nonhistone proteins. Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT. Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser 424 , which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4 c /PP4 R1 ). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1-122) was both necessary and sufficient for HDAC3-PP4 c interactions. Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4 c , unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4 c . These findings therefore further highlight the importance of protein-protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.

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Protein Phosphatase 4 Is a Positive Regulator of Hematopoietic Progenitor Kinase 1

Cited by 42 publications

References 79 publications

Differential regulation and properties of MAPKs

Differential regulation and properties of MAPKs

Conditional Knockout Mice Reveal an Essential Role of Protein Phosphatase 4 in Thymocyte Development and Pre-T-Cell Receptor Signaling

Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4

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