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: In marked contrast to the response to DIF-1, for which the pyk2− mutant is totally unresponsive (Araki et al., 2012), the STATc response of pyk2− cells to hyperosmotic stress is only minimally diminished; relative to the parental Ax2 strain, there is just a 1-min delay in STATc activation, and a very similar plateau level is achieved (Figure 2A). This suggests that, in the case of stress but not DIF-1, another kinase is almost fully competent to subsume the function of Pyk2 as an activator of STATc. The logical candidate for this role is Pyk3; it has the most closely related kinase domain in the kinome (51% identity in the kinase domain, Supplemental Figure S4A), it is one of the five TKLs that autophosphorylate on tyrosine when expressed in E. coli, and two entirely independently constructed and analyzed strains for pyk3 (pyk3− strains, Supplemental Figure S2) show a 20–50% reduction in their sorbitol-induced activation of STATc (Figure 2A; Vu et al., 2014). This suggests that Pyk2 is partially able to substitute the function of Pyk3. However, the most striking result is observed with the double mutant, pyk2−/pyk3−. This strain is completely unresponsive to hyperosmotic stress–induced activation of STATc (Figure 2A).
Affiliation: College of Life Sciences, Welcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.