Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

Abstract

Mps one binder 1a (MOB1A) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers. Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a Δ/Δ 1b tr/+ or Mob1a Δ/+ 1b tr/tr mice results in tumor development. Because most of these cancers resembled trichilemmal carcinomas, we generated doublemutant mice bearing tamoxifen-inducible, keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b (kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation, apoptotic resistance, impaired contact inhibition, enhanced progenitor self renewal, and increased centrosomes. Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1. Similarly, YAP1 was activated in some human trichilemmal carcinomas, and some of these also exhibited MOB1A/1B inactivation. Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis, and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway.

Mechanisms of Hippo pathway regulation

“…The interaction between YAP/TAZ and TEAD1-4 dissociates VGLL4 from TEAD1-4 and thereby activates TEAD-mediated gene transcription to promote tissue growth and inhibit apoptosis (Koontz et al 2013). Mouse models with deletion of MST1/2, SAV1, MOB1A/B, NF2, or LATS1/2 or YAP overexpression all exhibit upregulation of TEAD target gene expression, increased expansion of progenitor cells, and tissue overgrowth (Camargo et al 2007;Dong et al 2007;Zhou et al 2009;Cai et al 2010;Lee et al 2010;Lu et al 2010;Song et al 2010;Zhang et al 2010;Nishio et al 2012;Chen et al 2015b), supporting the functional roles of these genes in the Hippo pathway.…”

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

“…In these aggregation experiments, LATS1/LATS2 knockdown cells were found to maintain high levels of Cdx2 despite their positioning, whereas the wild-type inner cells did not. The knockout of both Mob1a and Mob1b, which are regulators of LATS1/2 activity, also results in developmental defects, with embryos arresting at around embryonic day (E) 6.5, prior to gastrulation (Nishio et al, 2012). Analysis of MOB1A/B-deficient blastocysts revealed aberrant nuclear YAP localization and modest growth failure in the ICM region, with few defects associated with the TE.…”

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

“…MOB1A and MOB1B share 95% amino acid identity, are substrates of the ubiquitin ligase PRAJA2 (26), and are commonly decreased in tumors. hMOB1A is mutated in melanoma and breast cancer cell lines and down-regulated in human colorectal, nonsmall cell lung, and skin cancers (27,28). Surprisingly, impaired MOB1 phosphorylation occurs in 81% of human liver cancers (17), and elevated YAP1 is now an independent prognostic marker for these malignancies (29).…”

“…In mice, MOB1B can compensate for loss of MOB1A, and vice versa, but loss of both Mob1a and Mob1b is embryonic-lethal (28). Mice partially deficient for Mob1a/1b develop tumors, most often skin cancers (28). However, the physiological functions of MOB1A/1B in liver are unknown, and the liver abnormalities of NF2-, SAV1-, or MST1/2-deficient mice had been thought to be independent of MOB1A/1B and LATS1/2 (17).…”