This chapter focuses on signaling pathways that regulate growth and differentiation of adult stem cells. The POU domain containing transcription factor Oct-4, previously known as Oct-3/4, confers ESC self-renewal and pluripotency. As embryonic stem cells (ESC) differentiate and lose pluripotency, expression of Oct-4 is downregulated. Subsequent overexpression allows cells to regain the ESC primitive phenotype, indicating this marker alone can reprogram self-renewal mechanisms. Oct-4 is composed of two isoforms, Oct-4 A and Oct-4B. These have identical central POU DNA binding domains and C-terminal domains, but differ in the N-terminal domains. The A isoform resides in the nucleus, possesses a functional N-terminal transactivation domain, and induces target gene expression, while the B isoform is cytoplasmic and has no transactivation domain. Signaling of the Wnt pathway is regulated by interactions between several key proteins, including glycogen synthase kinase-3β (GSK-3β), β-catenin, and T cell factor-4 (Tcf-4). The rate-limiting signaling node in this pathway is GSK-3β, a serine-threonine kinase with two isoforms. The alpha isoform (51 kDa) is a key regulator of glucose metabolism, while the beta form (47 kDa) mediates Wnt signaling through β-catenin. The kinase activity of glycogen synthase kinase (GSK)-3β is regulated by phosphorylation on Tyr216 and Ser9. Tyr216 phosphorylation increases the kinase catalytic activity of GSK-3β, while phosphorylation of Ser9 decreases GSK-3β activity. GSK-3β has a role in a wide variety of disease processes so it has been a key target for drug discovery efforts that have produced more than 30 small molecule inhibitors of GSK-3β with different ranges of specificity.
|Original language||English (US)|
|Title of host publication||Handbook of Cell Signaling, Second Edition|
|Number of pages||9|
|State||Published - Jan 1 2009|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)