Dual regulation of a <i>Dictyostelium</i> STAT by cGMP and Ca2+ signalling

Araki, Tsuyoshi; Egmond, Wouter N. van; Haastert, Peter J.M. van; Williams, Jeffrey

doi:10.1242/jcs.064436

Cited by 15 publications

(39 citation statements)

References 17 publications

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“…Instead, the elevation of intracellular Ca 2+ levels, which is also a potent STATc activating signal, activates PTP3 serine phosphorylation. Therefore, two parallel pathways are possible for the activation of STATc by osmotic stress (Araki et al. 2010).…”

Section: Dd‐statcmentioning

confidence: 99%

STAT signaling in Dictyostelium development

Kawata

2011

Dev Growth Differ

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Signal transducers and activators of transcription (STAT) proteins are one of the important mediators of phosphotyrosine-regulated signaling in metazoan cells. These proteins are components of JAK ⁄ STAT signal transduction pathways, which regulate immune responses, cell fate, proliferation, cell migration, and programmed cell death in multicellular organisms. The cellular slime mould, Dictyostelium discoideum, is the simplest multicellular organism using molecules homologous to STATs, Dd-STATa-d. The Dd-STATa null mutant displays delayed aggregation, no phototaxis and fails culmination. Here, the functions of Dictyostelium STATs during development and their associated signaling molecules are discussed.

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Section: Dd‐statcmentioning

confidence: 99%

STAT signaling in Dictyostelium development

Kawata

2011

Dev Growth Differ

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“…An ortholog of the mammalian E3 ubiquitin ligase Cbl, CblA, was found to act as a positive regulator of STATc phosphorylation by down-regulating PTP3 [14]. Exposure to hyperosmotic stress or to agents that elevated intracellular Ca 2+ levels induced phosphorylation of S448 and S747 of PTP3 and inhibited its enzymatic activity [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of the Protein Kinases Pyk3 and Phg2 as Regulators of the STATc-Mediated Response to Hyperosmolarity

Araki

et al. 2014

PLoS ONE

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Cellular adaptation to changes in environmental osmolarity is crucial for cell survival. In Dictyostelium, STATc is a key regulator of the transcriptional response to hyperosmotic stress. Its phosphorylation and consequent activation is controlled by two signaling branches, one cGMP- and the other Ca2+-dependent, of which many signaling components have yet to be identified. The STATc stress signalling pathway feeds back on itself by upregulating the expression of STATc and STATc-regulated genes. Based on microarray studies we chose two tyrosine-kinase like proteins, Pyk3 and Phg2, as possible modulators of STATc phosphorylation and generated single and double knock-out mutants to them. Transcriptional regulation of STATc and STATc dependent genes was disturbed in pyk3−, phg2−, and pyk3−/phg2− cells. The absence of Pyk3 and/or Phg2 resulted in diminished or completely abolished increased transcription of STATc dependent genes in response to sorbitol, 8-Br-cGMP and the Ca2+ liberator BHQ. Also, phospho-STATc levels were significantly reduced in pyk3− and phg2− cells and even further decreased in pyk3−/phg2− cells. The reduced phosphorylation was mirrored by a significant delay in nuclear translocation of GFP-STATc. The protein tyrosine phosphatase 3 (PTP3), which dephosphorylates and inhibits STATc, is inhibited by stress-induced phosphorylation on S448 and S747. Use of phosphoserine specific antibodies showed that Phg2 but not Pyk3 is involved in the phosphorylation of PTP3 on S747. In pull-down assays Phg2 and PTP3 interact directly, suggesting that Phg2 phosphorylates PTP3 on S747 in vivo. Phosphorylation of S448 was unchanged in phg2− cells. We show that Phg2 and an, as yet unknown, S448 protein kinase are responsible for PTP3 phosphorylation and hence its inhibition, and that Pyk3 is involved in the regulation of STATc by either directly or indirectly activating it. Our results add further complexities to the regulation of STATc, which presumably ensure its optimal activation in response to different environmental cues.

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“…What of Pyk3? Of interest, GbpC, the cGMP-binding protein that partially mediates the stress response ( Araki et al. , 2010 ), also translocates to cortex after stress ( Kortholt, van Egmond, et al.…”

Section: Discussionmentioning

confidence: 99%

“…The signaling pathway upstream of PTP3, on the phosphatase arm of the STATc stress activation pathway, is in part understood. Pharmacological evidence suggests that calcium signaling stimulates the two serine kinase activities that down-regulate PTP3 ( Araki et al. , 2010 ).…”

Section: Introductionmentioning

confidence: 99%