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. 2022 Sep 12;10:1012193. doi: 10.3389/fcell.2022.1012193

FIGURE 2.

FIGURE 2

Biological functions of REG4. REG4 indirectly interacts with epidermal growth factor receptor (EGFR) to phosphorylate and activate Akt, which induces activator protein-1 (AP-1)–mediated transcriptional initiation by an AP-1/c-Jun/JunA/JunB complex and glycogen synthase kinase three β (GSK3β)–β-catenin–transcription factor 4 (TCF-4) signaling. Additionally, REG4 can bind to G protein-coupled receptor 37 (GPR37) to activate EGFR. REG4 interacts with CD44 to activate regulated transmembrane proteolysis of CD44 resulting in γ-secretase–mediated cleavage and release of the CD44 intracytoplasmic domain (CD44ICD). TCF-4 and CD44ICD serve as transcriptional activators that up-regulate the expression of cyclins for cell-cycle progression. CD44ICD-mediated Kruppel-like factor 4 (Klf4) and SRY-box transcription factor 2 (SOX2) expression is involved in cancer stemness. Activator protein-1–induced overexpression of B cell lymphoma-extra large (Bcl-xL), B cell lymphoma 2 (Bcl-2), survivin, and matrix metalloproteinase-7 (MMP7) plays an important role in apoptosis, angiogenesis, invasion, and metastasis.