title: Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways.
abstract: When Dictyostelium cells are hyperosmotically stressed, STATc is activated by tyrosine phosphorylation. Unusually, activation is regulated by serine phosphorylation and consequent inhibition of a tyrosine phosphatase: PTP3. The identity of the cognate tyrosine kinase is unknown, and we show that two tyrosine kinase-like (TKL) enzymes, Pyk2 and Pyk3, share this function; thus, for stress-induced STATc activation, single null mutants are only marginally impaired, but the double mutant is nonactivatable. When cells are stressed, Pyk2 and Pyk3 undergo increased autocatalytic tyrosine phosphorylation. The site(s) that are generated bind the SH2 domain of STATc, and then STATc becomes the target of further kinase action. The signaling pathways that activate Pyk2 and Pyk3 are only partially overlapping, and there may be a structural basis for this difference because Pyk3 contains both a TKL domain and a pseudokinase domain. The latter functions, like the JH2 domain of metazoan JAKs, as a negative regulator of the kinase domain. The fact that two differently regulated kinases catalyze the same phosphorylation event may facilitate specific targeting because under stress, Pyk3 and Pyk2 accumulate in different parts of the cell; Pyk3 moves from the cytosol to the cortex, whereas Pyk2 accumulates in cytosolic granules that colocalize with PTP3.
authors.affiliation: College of Life Sciences, Welcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Araki
authors.affiliation: Center for Biochemistry, Institute of Biochemistry I, 50931 Cologne, Germany.
authors.forename: Linh Hai
authors.initials: LH
authors.lastname: Vu
authors.affiliation: Department of Biology, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Sasaki
authors.affiliation: Department of Biology, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kawata
authors.affiliation: Center for Biochemistry, Institute of Biochemistry I, 50931 Cologne, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Eichinger
authors.affiliation: College of Life Sciences, Welcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom j.g.williams@dundee.ac.uk.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Williams
mesh_terms: D004023:Dictyostelium / Q000201:enzymology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
chemical_list: D050791:STAT Transcription Factors; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases