Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling.
When 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 membrane-permeable 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 semi-constitutive tyrosine kinase that phosphorylates STATc, whereas parallel, stress-induced Ca(2+) signalling represses STATc dephosphorylation through its inhibitory effect on PTP3.
University of Dundee, College of Life Sciences, Dow Street, Dundee DD1 5EH, UK.
Tsuyoshi
T
Araki
Wouter N
WN
van Egmond
Peter J M
PJ
van Haastert
Jeffrey G
JG
Williams
D000595:Amino Acid Sequence; D000818:Animals; D045163:Antibodies, Phospho-Specific / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006152:Cyclic GMP / Q000378:metabolism*; D004023:Dictyostelium / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009997:Osmotic Pressure; D010766:Phosphorylation; D010768:Phosphoserine / Q000276:immunology; D010769:Phosphothreonine / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D013312:Stress, Physiological
D045163:Antibodies, Phospho-Specific; D015800:Protozoan Proteins; D050791:STAT Transcription Factors; C426825:STATc protein, Dictyostelium; D010769:Phosphothreonine; D010768:Phosphoserine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D006152:Cyclic GMP; D002118:Calcium