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Review
. 2020 Aug 27;12(9):2438.
doi: 10.3390/cancers12092438.

Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Sahar Sarmasti Emami  1 , Derek Zhang  1 , Xiaolong Yang  1
Affiliations
Review

Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Sahar Sarmasti Emami et al. Cancers (Basel). .

Abstract

The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

Keywords: Hippo pathway; LATS; MST; TAZ; YAP; protein phosphatase; tumorigenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Core components of the Hippo pathway in mammalian cells. When the Hippo pathway is ON, MST1/2 and MAP4K are activated, which subsequently phosphorylate and activate LATS1/2 kinases. Activated LATS1/2 phosphorylate transcriptional coactivator YAP/TAZ, preventing entry into the nucleus by anchoring them to 14-3-3 protein and/or promoting their degradation in the cytoplasm. This interrupts their interactions with the TEAD family of transcription factors, which subsequently change the transcription of downstream genes. When the Hippo pathway is OFF, YAP/TAZ upstream kinases are inactivated, which results in translocation of YAP/TAZ into the nucleus to interact with TEAD transcription factor to activate downstream target genes.
Figure 2
Figure 2
Classification of phosphatase superfamily. Protein phosphatases were classified into six different families according to the catalytic domains. PPP, phosphoprotein protein phosphatase family; PTPs, protein tyrosine phosphatase domain family; PPM, protein phosphatase 2C-like domain family; HAD, Haloacid dehalogenase-like hydrolase domain family; PPTD2, distal PTP domain; LPs, lipid domain family; NUDT, NUDIX hydrolase domain family. Numbers in parenthesis represent numbers of genes in each family.
Figure 3
Figure 3
Interaction of the Hippo pathway and phosphatases in tumorigenesis. PSPs (PP2A/PR55α, PP1, PP1A, POPX2, and MYPT1; gene symbols with orange background) and PTPs (SHP2/PTPN1, PTPN14, PTPN21, CDC14, PTEN; gene symbols with yellow background) can regulate tumorigenesis through positive or negative regulation of the Hippo pathway (gene symbols with purple background). Dotted blue lines includes core components of the Hippo pathway (MST1/2, MAP4Ks, SAV1, MOB1, LATS1/2, and YAP/TAZ). In addition, the Hippo pathway can directly or indirectly regulate several phosphatases (PP2A, CDC25, and PTEN; dotted orange lines).
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