YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

Abstract

Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.colorectal cancer | adenomatous polyposis coli | IL-6ST/gp130 | YAP | STAT3

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 179 ] Tumor cells interact with the ECM via Integrins, which respond to ligand binding and mechanical stress by signaling through FAK and SRC family kinases [ 180–182 ] to inhibit Hippo signaling and activate YAP/TAZ. [ 31,61,183‐199 ] SRC family kinases appear to act primarily by direct tyrosine phosphorylation of LATS1, but can also directly phosphorylate YAP/TAZ. [ 30,31,61,183‐199 ] Importantly, there is extensive signaling cross‐talk between Integrin‐SRC signaling and Growth factor‐PI3K‐Akt signaling.…”

“…[ 31,61,183‐199 ] SRC family kinases appear to act primarily by direct tyrosine phosphorylation of LATS1, but can also directly phosphorylate YAP/TAZ. [ 30,31,61,183‐199 ] Importantly, there is extensive signaling cross‐talk between Integrin‐SRC signaling and Growth factor‐PI3K‐Akt signaling. [ 200–206 ] In addition, mechanotransduction via Integrin‐SRC signaling also promotes formation of focal adhesions and stress fibers, a process involving increased Rho GTPase mediated actomyosin contractility.…”

“…Pro‐inflammatory cytokines, such as IL‐6, signal via cytokine receptors and the JAK‐STAT3 pathway. [ 272,273 ] There is evidence for cooperation and positive feedback between IL‐6 signaling and YAP/TAZ during intestinal regeneration and tumor formation, [ 30,193 ] in pancreatic cancer, [ 84 ] in renal cell carcinoma, [ 196 ] and in lung cancer. [ 198 ] There is also evidence for cross‐talk between cytokine signaling and pro‐inflammatory GPCR signaling [ 229 ] (Figure 2).…”

“…Broad spectrum SRC family tyrosine kinase inhibitors such as dasatinib potently inhibit YAP/TAZ activation [ 31,61,183,185‐190,195,281 ] and are effective in treating tumors in mice, [ 180,188,193,282 ] but suffer from toxicity in patients owing to inhibition of many other tyrosine kinases. Thus, there is a major unmet need for new and highly specific SRC family kinase inhibitors that are well tolerated.…”

YAP Aggravates Inflammatory Bowel Disease by Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis

“…As a key transcription coactivator, YAP (Yes-associated protein) plays a vital role in the Hippo pathway and is well established to promote tumor formation (Murakami et al, 2017;Taniguchi et al, 2017;Wang et al, 2016a;Yimlamai et al, 2014). YAP is reported to be highly associated with inflammationrelated diseases, including atherosclerosis (Wang et al, 2016b) and pancreatitis (Murakami et al, 2017).…”