The Hippo Tumor Suppressor Pathway (YAP/TAZ/TEAD/MST/LATS) and EGFR-RAS-RAF-MEK in cancer metastasis

Abstract

Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth. This pathway is activated in response to cell cycle arrest signals (cell polarity, transduction, and DNA damage) and limited by growth factors or mitogens associated with EGF and LPA. The major pathway consists of the central kinase of Ste20 MAPK ( Saccharomyces cerevisiae ), Hpo ( Drosophila melanogaster ) or MST kinases (mammalian) that activates the mammalian AGC kinase dm Wts or LATS effector (MST and LATS). YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation (TEA domain family, TEAD1-4), stem cells (Oct4 mononuclear factor and SMAD-related TGFβ effector), differentiation (RUNX1), and Cell cycle/apoptosis control (p53, p63, and p73 family members). This is due to the diverse roles of YAP and may limit tumor progression and establishment. TEAD also coordinates various signal transduction pathways such as Hippo, WNT, TGFβ and EGFR, and effects on lack of regulation of TEAD cancerous genes, such as KRAS, BRAF, LKB1, NF2 and MYC, which play essential roles in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. However, RAS signaling is a pivotal factor in the inactivation of Hippo, which controls EGFR-RAS-RAF-MEK-ERK-mediated interaction of Hippo signaling. Thus, the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.

The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases

“… 100 Eventually, IkBδ is derived from the p100 fragment containing ankyrin, which generates negative feedback on the main NF-kB signaling. 101 , 102 …”

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

“…Another example relates to the crosstalk between EGFR and the Hippo/YAP pathway. This pathway is the main route regulating tissue enlargement and organ size, and it is activated in response to cell cycle arrest and downstream signaling to RAS [ 104 ]. Essentially, the Hippo pathway controls a kinase cascade that inactivates Yes-associated protein (YAP), which plays central roles in the progression of cervical cancer.…”

Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation

“…In addition, we found that TEAD family was influenced on the immune cells. Reports have demonstrated that TEAD could coordinate several signal pathways such as Hippo, EGFR, Wnt and TGFβ [38]. The abnormal expression of TEAD could modulate several cancer-associated genes, including MYC, KRAS, NF2, BRAF and LKB1, which had crucial roles in the regulation of tumor immunity [39].…”