The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals

Abstract

The conserved Hippo signaling pathway regulates organ size in both Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using liver-specific conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotype was largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

“…In a similar fashion, Nf2 +/-mice have increased sensitivity to the carcinogenic effect of inhaled asbestos [120], and conditional deletion of Nf2 in mesothelial cells cooperates with loss of Ink4a/Arf and p53 to drive malignant mesothelioma [121]. Biallelic loss of Merlin in the liver was recently shown to result in hepatomegaly and formation of malignant tumours [17,18]. Although the issue has not been completely resolved, it seems that biallelic Nf2 loss in the liver leads to the expansion of a progenitor population able to differentiate at least partly along the ductal lineage [99].…”

“…In one variant of this model, Merlin is recruited to nascent adherens junctions by binding to α-catenin [16] and acti- [16] and actiand activates the canonical Hippo kinase cascade through Kibra [18,91]. In the other variant, Merlin fosters maturation of adherens junctions [16], enabling α-catenin to bind to 14-3-3 and thereby to the phosphorylated inactive form of YAP [92].…”

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

“…In addition, the function of a given Hippo component may differ in different tissues or even in different studies. For example, Benhamouche et al (14) reported that the liver phenotype of Nf2 −/− mice depends on NF2-EGFR signaling rather than on the NF2-MOB1-LATS-YAP1 pathway, but another study found that the Nf2 −/− liver phenotype could be rescued by heterozygous deletion of Yap1 (23). Similarly, the skin phenotype associated with abnormal Hippo signaling depends on SAV1 (16) and YAP1, but is independent of MST1/2 (24).…”

A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis

“…Yap flox and Sav1 flox mice have been published Zhang et al 2010). Mammary gland-specific knockout mice were generated by breeding Yap flox or Sav1 flox mice with MMTV-Cre (line F) mice (Wagner et al 1997) obtained from the National Cancer Institute Mouse Repository.…”