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  • Hippo signaling is unique in that it

    2022-01-21

    Hippo signaling is unique in that it does not possess a cognate ligand and receptor system. Instead, numerous upstream sensors that monitor cell morphology, cell polarity, cell-cell contact, and mechanical stress impinge onto the Hippo pathway core kinases, MST, and LATS. This in turn indicates the presence of a molecule(s) that couples upstream sensors and the Hippo pathway components. Merlin, the product of the NF2 (neurofibromatosis type 2) tumor suppressor gene, is one such molecule that links cell density and Hippo signaling (Hamaratoglu et al., 2006, Zhang et al., 2010). In desipramine sale at a high density, Merlin is hypophosphorylated and is associated with the CD44 cytoplasmic domain (Morrison et al., 2001). CD44-Merlin interaction recruits LATS to stimulate Hippo signaling that promotes contact inhibition (Yin et al., 2013). As cell density decreases, PAK (p21-activated kinase) phosphorylates Merlin, which leads to dissociation of Merlin from CD44 and subsequent cytoplasmic localization, thereby canceling the growth-suppressive actions of Merlin (Kissil et al., 2002, Surace et al., 2004). The present study revealed that, in addition to Merlin, PAR1b also couples CD44 and Hippo signaling. PAR1 was originally identified as one of six PAR proteins, each of which plays an essential role in the establishment of cell polarity during Caenorhabditis elegans development (Kemphues et al., 1988). In mammals, PAR1 was independently discovered as MARK (Drewes et al., 1997). The mammalian PAR1/MARK family comprises four isoforms. It has already been reported that Drosophila Par1 and mammalian PAR1d interact with Hpo and MST, respectively, and thereby inhibit Hpo/MST kinase activity through phosphorylation, indicating that Par1/PAR1 play a pro-oncogenic role by negatively regulating Hippo signaling (Huang et al., 2013, Heidary Arash et al., 2017). Drosophila Par1 inhibits Hpo by phosphorylating Ser30, which is conserved in mammalian MST2 but not in MST1, and we found in this work that PAR1b inhibits MST1 and MST2 by phosphorylating Thr440 and Ser444, respectively. Controversially, LKB1-mediated PAR1 activation has been reported to stimulate MST and LATS and thereby promote Hippo signaling (Mohseni et al., 2014). Although these observations may not be easily reconciled, this study provides a clue to the seemingly opposing roles of PAR1 in Hippo signaling regulation. In the absence of HMW-HA or in the dominance of LMW-HA over HMW-HA, cytoplasmic PAR1 inhibits Hippo signaling by suppressing MST through complex formation. In the presence of HMW-HA, however, membrane sequestration of PAR1b by the CD44-CD44 complex not only liberates MST for Hippo signaling activation but also promotes organization and execution of the apical-basal polarity program, especially formation of the Scribble polarity complex, which promotes association of MST with LATS for Hippo signaling activation (Cordenonsi et al., 2011). Accordingly, the effect of PAR1b on Hippo signaling is determined by the size of hyaluronan. It is intriguing to speculate that the CD44 cytoplasmic domain serves as a molecular scaffold of PAR1b and Merlin to ensure cooperative activation of the Hippo pathway core kinases MST and LATS depending on cell density. The expression level of HYAL2, the major hyaluronidase that primarily degrades HMW-HA to LMW-HA, is higher in invasive and aggressive breast cancers than in normal breast tissues (Udabage et al., 2005). This work extends these clinical observations by showing that, among the various breast cancer types, HYAL2 is frequently overexpressed in TNBCs, which account for 10%–15% of all breast cancers and show poor prognosis compared to that of other breast cancer subtypes because of their aggressive behavior and lack of targeted therapies. A high level of HYAL2 expression in tumor cells is also associated with strong accumulation of YAP in the nucleus, indicating inactivated Hippo signaling. As expected, the sizes of hyaluronans secreted from breast cancer cells with elevated HYAL2 were substantially smaller than the sizes of those secreted from breast cancer cells without HYAL2 overexpression. Furthermore, the HYAL2high breast cancer group showed a poorer prognosis than that of the HYAL2low breast cancer group, and a tumor xenograft assay using nude mice showed that reduced expression of HYAL2 dampened in vivo tumorigenicity.