The Hippo Signaling Pathway Manipulates Cellular Senescence

Abstract

The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases. A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation.

Keywords: Hippo pathway; cancer; cellular senescence.

Figure 1

Effects of the Hippo pathway on cellular senescence [30,31,34,35,37,38,40,44,47,51,53]. Factors associated with the Hippo pathway contribute to cellular senescence by regulating a number of molecules. MST1/2 and LATS1/2 promote senescence, whereas YAP/TAZ promote and inhibit senescence depending on the molecules associated. TEAD contributes to the expression of molecules that inhibit senescence. Arrows and perpendicular bars indicate potentiating and inhibitory effects.

Figure 2

Regulation of SASP factor expression by the Hippo pathway [23,25,94,95,96,97,98,104,105,106,107,108,109,110,111,112,113,114,115,117,121,126,127]. LATS1/2, MST 1/2, and YAP/TAZ regulate the expression of several interleukins and chemokines, which are SASP factors, via the transcription factors C/EBPβ and NF-κB. Hippo pathway-associated factors contribute to cellular senescence by regulating the expression of SASP factors through a number of molecules. Arrows and vertical bars indicate potentiating and inhibitory effects. Dashed lines indicate potential.

Figure 3

Relationship between the Hippo pathway and aging-related diseases [57,120,135,136,140,146,147,148,150]. The Hippo pathway is involved in physical aging by regulating cellular senescence in tissues. Arrows indicate potentiation and dashed lines indicate potential.