DYRKs are a new family of dual-specificity tyrosine-regulated kinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival. Regarding the DYRK3 kinase domain, intactness of Tyr(333) (but not Tyr(331)) within subdomain loop VII-VIII was critical for activation. Tyr(331) plus Tyr(333) acidification (Tyr mutated to Glu) was constitutively activating, but kinase activity was not affected substantially by unique N- or C-terminal domains. In transfected 293 and HeLa cells, DYRK3 was discovered to efficiently stimulate CRE-luciferase expression, to activate a CREB-Gal4 fusion protein, and to promote CREB phosphorylation at Ser(133). Interestingly, this CREB/CRE response was also supported (50% of wild-type activity) by a kinase-inactive DYRK3 mutant as well as a DYRK3 C-terminal region and was blocked by protein kinase A inhibitors, suggesting functional interactions between protein kinase A and DYRK3. Finally, DYRK3 expression in cytokine-dependent hematopoietic FDCW2 cells was observed to inhibit programmed cell death. Thus, primary new insight into DYRK3 kinase signaling routes, subdomain activities, and possible biofunctions is provided.