Hippo signaling is activated when mechanical tension is imposed by the surrounding microenvironment, and serves to shut down cell proliferation under conditions of high cell density. Core components of the Hippo pathway include the upstream MST kinases, downstream LATS kinases, and the adaptor proteins SAV1 (also called WW45) and MOB. In humans, 7 MOB homologs have been identified but only 2 of them (MOB1A/1B) can bind to and strongly activate LATS kinases. However, until recently, the normal functions of MOB1A/1B proteins in vivo were unknown.

We generated Mob1A/1B double homozygous mutant mice but observed that they died at gastrulation, indicating that Mob1A/1B are essential for embryogenesis. Loss of the remaining WT Mob1 allele in Mob1a^Δ/Δ1b^+/- or Mob1a^Δ/+1b^-/- mutant mice resulted in the development of a variety of tumors, with most resembling trichilemmal carcinomas of hair follicles, one of the epithelial tubule structure organs. In vitro, MOB1A/1B-deficient cells exhibited hyperproliferation, apoptotic resistance, impaired contact inhibition, enhanced progenitor self-renewal, defective terminal differentiation, and an increase in centrosomes. Significantly, half of human trichilemmal carcinoma samples examined showed MOB1A/1B inactivation (JCI, 2012.12). We are currently analyzing the role of Hippo pathway in other epithelial tubule structure organs, such as bile ducts, bronchoalveolar cells, uterus, salivary glands, and mammary glands, and trying to find interesting phenotypes.