Figure 3. Schematic representation of signaling cascades that regulate ΔNp63α and the drugs that have been shown to target them.

Several signaling cascades have been implicated in the regulation of ΔNp63α. In Wnt/β-catenin signaling, Wnt binds to Frizzled receptors, leading to the formation of a larger cell surface complex with LRP. Activation of the Wnt receptor complex triggers displacement of GSK-3β from the APC/Axin/GSK-3β-complex. β-catenin is translocated to the nucleus where it binds to LEF1 and transcriptionally activates ΔNp63α. α6β4 integrin interaction with TG2 or NRP1 leads to the activation of a kinase cascade that suppresses the Hippo signaling component LATS1, allowing YAP to enter the nucleus where it binds to ΔNp63α preventing proteasome degradation. Several compounds including the NRP1 inhibitor EG00229, the TG2 inhibitor NC9 or the diet derived compound Sulforaphane which inhibits TG2, and the YAP inhibitor Verteporfin can impair ΔNp63α protein expression. In addition to TG2, Sulforaphane can inhibit Interleukin driven JAK/STAT3 activation to suppress ΔNp63α expression. EGFR signaling also regulates ΔNp63α through STAT3. EGFR activation leads to phosphorylation and activation of the PI3K/AKT/mTOR pathway which phosphorylates STAT3, which binds to the promoter of ΔNp63α. CRBN, DDB1 and Cul4, form the E3 ubiquitin ligase complex CRL4^CRBN. Thalidomide analogues alter the CRL4^CRBN ubiquitin ligase to target ΔNp63α, resulting in its degradation in the presence of thalidomide. Abbreviations: AKT, alpha serine/threonine-protein kinase; AMOTL, angiomotin-like protein; AMPK, AMP-activated protein kinase; APC, adenomatous polyposis coli; CK1α, casein kinase 1α CRBN, cereblon; CUL4, cullin 4; DDB1, DNA damage binding protein 1; EGFR, epidermal growth factor receptor; ERK, extracellular signal related kinases; FAK, focal adhesion kinase; GIPC1m GIPC PDZ domain containing family member 1; JAK, janus kinase; LATS1, large tumor suppressor kinase 1; LRP, low-density lipoprotein receptor related protein; MEK, mitogen activated protein kinase kinase; mTOR, mammalian target of rapamycin; NRP1, Neuropilin 1; PDK1, pyruvate dehydrogenase kinase 1; PI3K, phosphatidylinositol 3-kinase; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; STAT3, signal transducer and activator of transcription 3; STATTIC, STAT3 inhibitory compound; WNT, wingless and INT1; WWP1, WW domain containing E3 ubiquitin protein ligase 1.