A STAT-regulated, stress-induced signalling pathway in<i>Dictyostelium</i>

Araki, Tsuyoshi; Tsujioka, Masatsune; Abe, Tomoaki; Fukuzawa, Masashi; Meima, Marcel E; Schaap, Pauline; Morio, Takahiro; Urushihara, Hideko; Katoh, Masahiko; Maeda, Mineko; Tanaka, Yoshimasa; Takeuchi, Ikuo; Williams, Jeffrey

doi:10.1242/jcs.00501

Cited by 41 publications

(88 citation statements)

References 51 publications

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“…8-bromo-cGMP activates STATc, that is, it induces its tyrosine phosphorylation, with kinetics that closely resemble the kinetics of the hyperosmotic STATc stress response (Araki et al, 2003). Consistent with cGMP playing an important role in the STATc stress response, 8-bromo-cGMP does not induce tyrosine phosphorylation and nuclear accumulation of STATc in a gbpC null strain ( Fig.…”

Section: Cgmp Regulation Of Statcsupporting

confidence: 56%

“…Like metazoan STAT1 (Gatsios et al, 1998), STATc is also activated when cells are exposed to hyperosmotic stress (Araki et al, 2003). The peak level of tyrosine phosphorylation of STATc is higher after stress than after DIF treatment and tyrosine phosphorylation is much more prolonged.…”

Section: Introductionmentioning

confidence: 99%

“…The peak level of tyrosine phosphorylation of STATc is higher after stress than after DIF treatment and tyrosine phosphorylation is much more prolonged. This might explain why stress induces the expression of a STATcdependent gene set, whereas DIF-1 fails to activate these genes (Araki et al, 2003). This is an important stress-response pathway in Dictyostelium; a recent microarray study indicated that 20% of all hyperosmotic-stress-induced genes are dependent for their activation on the presence of STATc (Na et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…We analyse the phosphorylation changes that are induced by stress and identify two sites of regulated phosphorylation. One of the known rapid responses to hyperosmotic stress is the accumulation of intracellular (Kuwayama et al, 1996;Araki et al, 2003). GbpC is a cGMP-binding protein that contains Ras, mitogenactivated protein kinase kinase kinase (MAPKKK) and Ras guanine nucleotide exchange factor (GEF) domains (Goldberg et al, 2002;Goldberg et al, 2006;.…”

Section: Introductionmentioning

confidence: 99%

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Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling

Araki

Egmond

Haastert

et al. 2010

Journal of Cell Science

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SummaryWhen cells are exposed to hyperosmotic stress, the Dictyostelium STAT orthologue STATc is rapidly tyrosine phosphorylated. Previous observations suggest a non-paradigmatic mode of STAT activation, whereby stress-induced serine phosphorylation of the PTP3 protein tyrosine phosphatase inhibits its activity towards STATc. We show that two serine residues in PTP3, S448 and S747, are rapidly phosphorylated after osmotic stress. cGMP is a second messenger for hyperosmotic stress response and 8-bromo-cGMP, a membranepermeable form of cGMP, is a known activator of STATc. GbpC, a cGMP-binding Ras guanine nucleotide exchange factor protein, is a founder member of a protein family that includes LRRK2, the gene commonly mutated in familial Parkinson's disease. Genetic ablation of gbpC prevents STATc activation by 8-bromo-cGMP. However, osmotic-stress-induced activation of STATc occurs normally in the gbpC null mutant. Moreover, 8-bromo-cGMP does not stimulate phosphorylation of S448 and S747 of PTP3 in a wild-type strain. These facts imply the occurrence of redundant activation pathways. We present evidence that intracellular Ca 2+ is a parallel second messenger, by showing that agents that elevate intracellular Ca 2+ levels are potent STATc activators that stimulate phosphorylation of S448 and S747. We propose that stress-induced cGMP signalling exerts its stimulatory effect by potentiating the activity of a semiconstitutive tyrosine kinase that phosphorylates STATc, whereas parallel, stress-induced Ca 2+ signalling represses STATc dephosphorylation through its inhibitory effect on PTP3.

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Section: Cgmp Regulation Of Statcsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling

Araki

Egmond

Haastert

et al. 2010

Journal of Cell Science

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“…Dictyostelium STATc, like metazoan STATs 1 and 3 (12), can be activated by either ligand stimulation or hyperosmotic stress (13,14). The activating ligand for STATc is differentiation inducing factor (DIF-1), a chlorinated polyketide that is produced by the prespore cells and that induces prestalk-specific gene expression (15,16).…”

mentioning

confidence: 99%

Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

Araki

Kawata

Williams

2012

Proc. Natl. Acad. Sci. U.S.A.

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SH2 domains are integral to many animal signaling pathways. By interacting with specific phosphotyrosine residues, they provide regulatable protein-protein interaction domains. Dictyostelium is the only nonmetazoan with functionally characterized SH2 domains, but the cognate tyrosine kinases are unknown. There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs), a group of kinases which, despite their family name, are classified mainly as serine-threonine kinases. STATs are transcription factors that dimerize via phosphotyrosine-SH2 domain interactions. STATc is activated by phosphorylation on Tyr922 when cells are exposed to the prestalk inducer differentiation inducing factor (DIF-1), a chlorinated hexaphenone. We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. Conversely, overexpression of Pyk2 causes constitutive STATc activation. Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. This demonstration that a TKL directly activates a STAT has significant implications for understanding the evolutionary origins of SH2 domain-phosphotyrosine signaling. It also has mechanistic implications. Our previous work suggested that a predicted constitutive STATc tyrosine kinase activity is counterbalanced in vivo by the DIF-1-regulated activity of PTP3, a Tyr922 phosphatase. Here we show that the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation. Also, as predicted, Pyk2 is constitutively active as a STATc kinase. This observation provides further evidence for this highly atypical, possibly ancestral, STAT regulation mechanism. S H2 domains form part of a paradigmatic "writer/reader/ eraser" control module (1, 2) in which the writers are tyrosine kinases (TKs), the readers are SH2 domains, and the erasers are protein tyrosine phosphatases (PTPs). In principle no one element of such a three-component system can function usefully independently of the other two. So how could such a three-component system have evolved? Here the fungi and the amoebozoan Dictyostelium have been informative.Metazoa possess large numbers of TKs, but the only unicellular organisms known to possess them are choanoflagellates, unicellular close relatives of the Metazoa (3, 4). Although neither Dictyostelium nor fungi possess TKs, they do have PTPs, thus suggesting that tyrosine phosphorylation arose in a common ancestor of fungi and Amoebozoa, mediated perhaps by dualspecificity kinases and regulated by dephosphorylation via PTPs (2). There are no phosphotyrosine-binding SH2 domains in fungi, but there is a sequence-related domain within the SPT6 protein that binds phospho-serine and that may have been ancestral to modern SH2 domains (5). In the fungi, therefore, phosphorylation of tyrosine appears to be used solely as a direct modulator of enzymatic function, but in Dictyoste...

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Extracellular matrix family proteins that are potential targets of Dd-STATa in Dictyostelium discoideum

et al. 2004

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Dd-STATa is a functional Dictyostelium homologue of metazoan STAT (signal transducers and activators of transcription) proteins, which is activated by cAMP and is thereby translocated into the nuclei of anterior tip cells of the prestalk region of the slug. By using in situ hybridization analyses, we found that the SLF308 cDNA clone, which contains the ecmF gene that encodes a putative extracellular matrix protein and is expressed in the anterior tip cells, was greatly down-regulated in the Dd-STATa-null mutant. Disruption of the ecmF gene, however, resulted in almost no phenotypic change. The absence of any obvious mutant phenotype in the ecmF-null mutant could be due to a redundancy of similar genes. In fact, a search of the Dictyostelium whole genome database demonstrates the existence of an additional 16 homologues, all of which contain a cellulose-binding module. Among these homologues, four genes show Dd-STATa-dependent expression, while the others are Dd-STATa-independent. We discuss the potential role of Dd-STATa in morphogenesis via its effect on the interaction between cellulose and these extracellular matrix family proteins.

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A STAT-regulated, stress-induced signalling pathway inDictyostelium

Cited by 41 publications

References 51 publications

Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling

Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling

Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

Extracellular matrix family proteins that are potential targets of Dd-STATa in Dictyostelium discoideum

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