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

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Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. / Araki, Tsuyoshi; Kawata, Takefumi; Williams, Jeffrey G. (Lead / Corresponding author).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 28, 2012, p. E1931-E1937.

Research output: Contribution to journalArticle

Harvard

Araki, T, Kawata, T & Williams, JG 2012, 'Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling' Proceedings of the National Academy of Sciences of the United States of America, vol 109, no. 28, pp. E1931-E1937., 10.1073/pnas.1202715109

APA

Araki, T., Kawata, T., & Williams, J. G. (2012). Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. Proceedings of the National Academy of Sciences of the United States of America, 109(28), E1931-E1937. 10.1073/pnas.1202715109

Vancouver

Araki T, Kawata T, Williams JG. Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(28):E1931-E1937. Available from: 10.1073/pnas.1202715109

Author

Araki, Tsuyoshi; Kawata, Takefumi; Williams, Jeffrey G. (Lead / Corresponding author) / Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 28, 2012, p. E1931-E1937.

Research output: Contribution to journalArticle

Bibtex - Download

@article{f152595e4c604db79a6ea49c3a418444,
title = "Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling",
author = "Tsuyoshi Araki and Takefumi Kawata and Williams, {Jeffrey G.}",
year = "2012",
doi = "10.1073/pnas.1202715109",
volume = "109",
number = "28",
pages = "E1931--E1937",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

A1 - Araki,Tsuyoshi

A1 - Kawata,Takefumi

A1 - Williams,Jeffrey G.

AU - Araki,Tsuyoshi

AU - Kawata,Takefumi

AU - Williams,Jeffrey G.

PY - 2012

Y1 - 2012

N2 - 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 counter-balanced 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.

AB - 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 counter-balanced 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.

UR - http://www.scopus.com/inward/record.url?scp=84863901651&partnerID=8YFLogxK

U2 - 10.1073/pnas.1202715109

DO - 10.1073/pnas.1202715109

M1 - Article

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 28

VL - 109

SP - E1931-E1937

ER -

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