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. 2019 Dec 18;9(1):10. doi: 10.3390/cells9010010

Figure 2.

Figure 2

Dysregulation of alternative splicing sustains EGFR/EGFRvIII signaling and metabolism reprogramming in brain tumors. Stimulation of EGFR, and/or expression of the constitutive active EGFRvIII isoform, activates MYC-dependent expression of hnRNP proteins promoting alternative splicing of PKM2 and ΔMAX isoforms. High level of PKM2 and ΔMAX ensures high glycolytic flux and expression of GLUT1, GLUT3, PDK1 and HK2 genes, respectively, sustaining glucose-dependent cell proliferation. Concurrently, CD44s expression and PTBP1-mediated splicing of ANXA7-I2 isoform amplifies EGFR signaling by reducing lysosomal degradation of activated receptor. EGFR: epidermal growth factor receptor; EGFRvIII: epidermal growth factor receptor variant III; EGF: epidermal growth factor; hnRNPA1: heterogeneous nuclear ribonucleoprotein A1; hnRNPA2: heterogeneous nuclear ribonucleoprotein A2; PTBP1: Polypyrimidine tract-binding protein 1; SRSF3: serine and arginine rich splicing factor 3; PKM: pyruvate kinase; PKM2: pyruvate kinase isozymes M2; GLUT1: glucose transporter 1; GLUT3: glucose transporter 3; PEP: phosphoenolpyruvate; ANXA7: annexin A7; ANXA7-I2: annexin A7 isoform 2; PDK1: pyruvate Dehydrogenase Kinase 1; LDHA: lactate dehydrogenase A; HK2: hexokinase 2. MAX: myc-associated factor X; ΔMAX: delta myc-associated factor X.