Signaling Pathways Regulating Growth and Differentiation of Adult Stem Cells

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.