Signaling Pathways Regulating Growth and Differentiation of Adult Stem Cells

Larry Denner, Margaret Howe, Randall J. Urban

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations


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 languageEnglish (US)
Title of host publicationHandbook of Cell Signaling, Second Edition
Number of pages9
ISBN (Electronic)9780123741455
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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