Glycogen synthase kinase 3 (GSK3) plays important roles in Wnt and insulin signaling, cell fate determination, and Alzheimer-like tau phosphorylation. We discovered an isoform of tau protein kinase I (TPKI) / GSK3b with a 13 amino acid insert in the catalytic domain owing to alternative splicing. The alternative transcripts were found in the brains of the mouse, rat and human, with highly conserved sequences. The variant protein, named TPKI2 / GSK3b2, was abundant in the brain. Immunohistochemistry indicated differential distribution of the conventional and the new TPKI / GSK3b isoforms within young neurons. TPKI2 / GSK3b2 showed decreased kinase activities towards two phosphorylation sites on tau compared with the conventional isoform. Immunohistochemistry indicated that TPKI2 / GSK3b2 occurs predominantly in the neuronal soma, while TPKI1 / GSK3b1 is found both in the soma and processes. These results indicate that the new splice isoform has a different function. Because the amino acid insert occurs in the domain implicated in interaction with a protein phosphatase in a homologous kinase cdk-2, the alternative splicing can regulate multiprotein complex formation and function involving TPKI / GSK3b. Keywords: glycogen synthase kinase 3, protein kinase subdomain, splice variant, tau phosphorylation, tau protein kinase.

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