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J Biol Chem, Vol. 274, Issue 21, 15115-15126, May 21, 1999

Phosphorylation of the Transactivation Domain of Pax6 by Extracellular Signal-regulated Kinase and p38 Mitogen-activated Protein Kinase

From the Department of Biochemistry, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway

The transcription factor Pax6 is required for normal development of the central nervous system, the eyes, nose, and pancreas. Here we show that the transactivation domain (TAD) of zebrafish Pax6 is phosphorylated in vitro by the mitogen-activated protein kinases (MAPKs) extracellular-signal regulated kinase (ERK) and p38 kinase but not by Jun N-terminal kinase (JNK). Three of four putative proline-dependent kinase phosphorylation sites are phosphorylated in vitro. Of these sites, the serine 413 (Ser⁴¹³) is evolutionary conserved from sea urchin to man. Ser⁴¹³ is also phosphorylated in vivo upon activation of ERK or p38 kinase. Substitution of Ser⁴¹³ with alanine strongly decreased the transactivation potential of the Pax6 TAD whereas substitution with glutamate increased the transactivation. Reporter gene assays with wild-type and mutant Pax6 revealed that transactivation by the full-length Pax6 protein from paired domain-binding sites was strongly enhanced (16-fold) following co-transfection with activated p38 kinase. This enhancement was largely dependent on the Ser⁴¹³ site. ERK activation, however, produced a 3-fold increase in transactivation which was partly independent of the Ser⁴¹³ site. These findings provide a starting point for further studies aimed at elucidating a post-translational regulation of Pax6 following activation of MAPK signaling pathways.

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