The Hippo signaling pathway is a signaling cascade that plays a crucial role in regulating cell growth, proliferation, and organ size in mammals, including humans. It was initially discovered in Drosophila melanogaster (fruit flies) and later found to have similar functions in mammals. The Hippo pathway comprises several key components, including mammalian STE20-like kinase 1/2 (MST1/2), the protein Salvador homolog 1 (SAV1), MOB kinase activator 1A/B (MOB1A/B), large tumor suppressor kinase 1/2 (LATS1/2), Yes-associated protein 1 (YAP), Transcriptional coactivator with PDZ-binding motif (TAZ), and the transcriptional enhanced associated domain (TEAD) family. At its core, YAP and TAZ serve as canonical transcriptional coactivators and act as effectors within the Hippo pathway. When the Hippo pathway is inactivated, YAP and TAZ are not phosphorylated and translocate into the nucleus where they interact with transcriptional factors such as the TEAD family to regulate the expression of target genes involved in cell proliferation, survival, metastasis, and differentiation. Conversely, when the Hippo pathway is activated, MST1/2 kinases are activated and phosphorylated. The phosphorylated MST1/2 kinases then activate LATS1/2 kinases, enhancing their kinase activity. Subsequently, the activated LATS1/2 kinases phosphorylate YAP and TAZ, causing them to remain in the cytoplasm. Eventually, the phosphorylated YAP and TAZ bind to 14-3-3 proteins, which leads to their degradation. Moreover, dysregulation of the Hippo pathway has been implicated in various aspects of cancer development and progression, including tumor growth, metastasis, and resistance to therapy. Aberrant activation of YAP and TAZ can promote uncontrolled cell proliferation, inhibit apoptosis, and enhance tumor invasion and metastasis. Consequently, targeting components of the Hippo pathway is considered a potential strategy for therapeutic intervention. Therefore, it is considered that potential therapeutic strategies and further research are needed to regulate the excessively activated YAP and TAZ. In part I of this study, testis-specific serine/threonine kinase 1B (TSSK1B), a member of the calcium/calmodulin-dependent protein kinase (CAMK) superfamily, is identified as a negative regulator of YAP, suppressing cellular proliferation and oncogenic transformation. Two pathways were identified that inhibit YAP activity through phosphorylation. First, the liver kinase B1 (LKB1), a serine/threonine kinase, directly activates the TSSK1B kinase, leading to the phosphorylation of YAP at Ser94. Second, activated TSSK1B phosphorylates LATS1/2 kinases, indirectly phosphorylating YAP at Ser127. Additionally, xenograft experiments showed that TSSK1B-mediated phosphorylation resulted in suppressed tumor growth. These studies reveal that the LKB1–TSSK1B axis directly phosphorylates YAP at Ser94 and impedes tumor growth through anti-cancer effects. Part II of this study investigated the role of GPR54, a G protein-coupled receptor known to be overexpressed in triple-negative breast cancer (TNBC), to identify potential therapeutic targets for this highly aggressive and treatment refractory form of breast cancer. GPR54 activates Gαq/11 proteins, which in turn activate RhoA and inhibits the LATS1/2 kinases, leading to the activation of YAP. Moreover, this activation of YAP not only upregulates YAP target genes but also increases mRNA levels of GPR54 and KISS1 in MDA-MB-231 cells. Furthermore, GPR54 signaling triggers YAP/TAZ-dependent tumorigenic potentials, such as invasion, migration, proliferation, and anchorage-independent growth. These findings suggest that activation of YAP via GPR54 signaling establishes a positive feedback loop in TNBC, which promotes tumorigenic potential. Consequently, GPR54 signaling contributes to the growth and development of TNBC. Thus, targeting GPR54 to inhibit YAP activity could represent a promising therapeutic strategy for treating TNBC._x000D_
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<br>Keywords: Hippo-YAP pathway, YAP/TAZ, phosphorylation, TSSK1B, LKB1, LATS1/2, GPR54, Kisspeptin, GPCR, TNBC, RhoA, actin polymerization
