Figure 2.

Signaling pathways of the CD44 intracellular domain (CD44-ICD) under hypoxia. CD44 is cleaved in two steps. The first cleavage is promoted via proteolysis of the ectodomain by matrix metalloproteinases, among others, followed by a second cleavage of the transmembrane domain by presenilin-dependent γ-secretase, resulting in the release of CD44-ICD. The released CD44-ICD fragments translocate to the nucleus and activate various genes as a co-transcription factor for Runt-related transcription factor 2 (RUNX2). CD44-ICD also binds to cAMP response element-binding protein (CREB) to regulate the gene expression of cyclin D1 and oxidative glycolysis-related genes 3-phosphoinositide-dependent kinase 1 (PDK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4). Under hypoxic conditions, CD44-ICD binds to hypoxia-inducible factor (HIF)-2α and activates its expression, resulting in enhanced activation of HIF-2α target genes, including Sox2, NANOG, and OCT4, the genes of which are required for maintaining the stemness of GSCs. *: activated gene.