Therefore, it is important to understand the molecular mechanisms underlying the stemness maintenance. pathway in relevance to stem cell biology, and provide a thorough understanding in the tissue homeostasis and identification of potential targets to block tumor development. We also provide the regulatory role of tumor suppressor WWOX in the upstream of TGF-, Hyal-2, and Wnt signaling that cross talks with the Hippo pathway. (9, 10). Later, researchers uncovered more components within this pathway, including scaffolding protein Salvador (Sav) (11), Ste20-like kinase Hippo (Hpo) (12C14), and Mob as tumor suppressor (Mats) (15). These mutant proteins may cause tissue overgrowth in and mammals are matched by color. This network controls the transcriptional events for regulating Itgb3 cell proliferation, survival, and death. Table 1 Hippo pathway components and major functions. Hpo) phosphorylates LATS1/2 (or Wts) and MOB1 (or Mats) in a canonical manner, with the assistance of cofactor SAV1 (or Sav). SAV1 is a WW domain-containing protein needed for integrating the upstream signal(s). Then, the activated LATS1/2, in turn, triggers the phosphorylation of the major coactivators YAP/TAZ (two homologs of Yki) at multiple residues (Figure 1). Phosphorylation of YAP at S127 (corresponding to S89 on TAZ) promotes its binding with 14-3-3, thus resulting in the cytoplasmic retention (20). Phosphorylation of YAP/TAZ at S381 and S311, respectively, creates a binding site for casein Mogroside II A2 kinase 1 (CK1) and subsequent phosphorylation by CK1/ at the DSGxS motif. Then SCFTrCP, a multi-subunit SKP-CULLIN-F-box (SCF) ligase complex specifically recognizes the phosphodegron DpSGxpS of YAP and TAZ for leading to eventual YAP/TAZ ubiquitination and degradation (20, 50, 51). YAP protein is also degraded via Mogroside II A2 autophagy (52). Unphosphorylated YAP/TAZ complex translocates to the nucleus to drive transcriptional activation (Figure 2). The phosphorylation/degradation strategy has been seen in many biological molecules for their turnover. For example, tumor suppressor p53 is subjected to Mdm2-mediated degradation in the cytoplasm, whereas phosphorylated p53 is stabilized in the nucleus. MST1/2 in Hippo pathway can be activated without upstream kinases. The phosphorylation cascade is enhanced by MST1/2 dimerization (53). Active MST1/2 phosphorylates SAV1 and MOB1A/B (19, 29), which assists MST1/2 to recruit and phosphorylate LATS1/2 at their hydrophobic motifs (T1079 for LATS1 and T1041 for LATS2) (24, 54). Another key component in this action is NF2 (or Merlin), which directly interacts with LAST1/2 and promotes their phosphorylation (24). LATS1/2 subsequently undergoes autophosphorylation (18), and triggers the phosphorylation of YAP and TAZ for functional inactivation (55). Moreover, in parallel to MST1/2, two groups of MAP4Ks (mitogen-activated protein kinase kinase kinase kinase), MAP4K1/2/3/5 [homologs of (Hppy)] and MAP4K4/6/7 [homologs of (Msn)] directly phosphorylate LATS1/2 at their hydrophobic motifs and result in LATS1/2 activation, which consequently Mogroside II A2 inactivates YAP/TAZ (23, 56, 57). Overall, like many signaling pathways, the Hippo phosphorylation cascade is well-orchestrated and evolutionarily conserved. However, the ultimate outcome can be altered, either enhanced, or altered, by various signal stimulators. Conceivably, a single stimulator Wnt or growth factor, for example, may activate not Mogroside II A2 only the Hippo pathway but also other molecular paths, thereby either toning down or escalating the outcomes. Nonetheless, there are multiple signal initiators for the Hippo pathway. The signal flow could be in either a concerted manner or ends up in chaos. Among all the factors, how can those signals possibly work in a concert or contradictory manner? In short, GPCR either activates or inhibits the Hippo-YAP pathway depending on the signaling effected by the soluble Serum-borne lysophosphatidic acid and sphingosine 1-phosphophate (44). Soluble factor Amphiregulin binds EGFR and acts as an autocrine growth Mogroside II A2 factor for establishing a positive autocrine regulatory feedback loop between EGFR and YAP1, which is important in cancer progression (37). Cell junction proteins Echinoid and E-cadherin inhibit YAP/TAZ activation. Echinoid physically binds and stabilizes the Hpo-binding partner Sav at adherens junctions. Loss of Echinoid compromises Yki phosphorylation, resulting in elevated Yki.