Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways.
Bottom Line: 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.
Affiliation: College of Life Sciences, Welcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.Show MeSH
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Mentions: The interaction between Pyk2 and STATc can readily be demonstrated using Pyk2-GST fusion protein, produced in E. coli, as a binding substrate for STATc in a “pull-down” assay (Araki et al., 2012). The same holds true for Pyk3. In both cases there is a basal level of STATc binding to Pyk2 and Pyk3 that decreases somewhat after exposure to sorbitol (Figure 6A). Thus binding of STATc to the two kinases is semiconstitutive. The reason for a decrease is unclear, but one possibility is that some change in STATc, such as serine/threonine phosphorylation, is induced by high osmolarity, and this inhibits stress-induced binding to STATc in some unknown way. Interaction between Pyk2 and STATc occurs when STATc binds to a site or sites of tyrosine autophosphorylation on Pyk2 (Araki et al., 2012). When a similar experiment is performed using GST-Pyk3 and its kinase-dead form rather than GST-Pyk2, it yields identical results (Figure 6A).
Affiliation: College of Life Sciences, Welcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.