Fig. 4

Frequently altered signaling pathways in SCLC. a The Hippo signaling pathway discriminates between active (ON) and inactive (OFF) states. When Hippo signaling is on, the phosphorylation of SAV1 is mediated by MST1/2, both further activating MOB1A/B and LATS1/2 via phosphorylation. Ultimately, the YAP/TAZ complex is phosphorylated and degraded, resulting in transcriptional repression. Or in contrast, when Hippo signaling is off, the phosphorylation cascade does not take place. The YAP/TAZ complex translocates into the nucleus and interacts with TEAD, leading to transcriptional activation. b The Notch signaling pathway is mediated between signal-sending and signal-receiving cells via interaction of the Notch receptor and a Notch ligand (DLL or JAG). Consecutively, the Notch receptor is cleaved; NICD translocates into the nucleus and activates the transcription of target genes in signal-receiving cells (e.g. HES, HEY, and MYC). ASCL1 is categorized as a master regulator of NE differentiation via high expression of the non-functional DLL3 at the golgi apparatus. DLL3 acts as a dominant-negative inhibitor of Notch signaling and orchestrates the degradation of other Notch members. HES and HEY family members encode transcriptional repressors of ASCL1. Notch negatively regulates NE differentiation in SCLC. High ASCL1 expression levels significantly correlate with NE differentiation. c Hedgehog signaling is activated by the binding of SHH to PTCH1. This leads to the shift of inhibitory activity towards SUFU (green path). Subsequently, the GLI1 monomer translocates into the nucleus and promotes gene transcription. When PTCH1 exerts its inhibitory effects against SMO, SUFU and GLI1 build a complex which inactivates the expression of HH target genes (red path). d Epigenetic reprogramming plays an instrumental role in SCLC via methylation / acetylation of DNA/histones. Key chromatin modifiers are EZH2, the CREBBP/EP300 complex, and the KMT2 family proteins which each target the amino acids K27, K18, or K4 of histone 3, respectively. Created with BioRender.com. ASCL1 - Achaete-scute homologue 1; DLL3 - Delta-like protein 3; REST - RE1-silencing transcription factor; HES - HES family BHLH transcription factor 1; HEY - HES-related repressor protein 1; MYC - MYC proto-oncogene; CYCD1 - Cyclin D1; p21 - Cyclin dependent kinase inhibitor 1A; MOB1A/B - MOB kinase activator 1A/B; MST1/2 - Mammalian sterile 20-like kinases 1 and 2; LATS1/2 - Large tumor suppressor kinase 1/2; SAV1 - Salvador homolog 1; YAP1 - Yes-associated protein 1; TAZ - Tafazzin family protein; TEAD - TEA domain transcription factor; EZH2 - Enhancer of zeste homolog 2; Me - Methylation; Ac - Acetylation; CREBBP - CREB binding protein; EP300 - E1A binding protein P300; H2A/2B/3/4 - Histone 2A/2B/3/4; KMT2 - Lysine methyltransferase 2; SHH - Sonic hedgehog; GLI1 - GLI family zinc finger 1; SUFU - SUFU negative regulator of hedgehog signaling; PTCH1/2 - Patched 1; SMO - Smoothened, frizzled class receptor; BCL2 - B-cell lymphoma 2; SOX2 - SRY-box transcription factor 2