The Hippo signalling pathway and its implications in human health and diseases

Abstract

As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

Fig. 1

A timeline of essential discoveries and processes of the Hippo pathway. These discoveries were made initially in 1995 and then gradually to the present. The discoveries mainly focus on two aspects, including the components and processes of Hippo pathway and the function of Hippo pathway in physiological and pathological conditions

Fig. 2

The core Hippo pathway in mammals. STRIPAK complex in the upstream regulates both MST1/2 and MAP4Ks. MAP4Ks or MST1/2 and its scaffold protein SAV1 could phosphorylate LATS1/2 and its scaffold MOB1 with the help of WWC1–3. The phosphorylated MOB1 can also directly promote the activation of LATS1/2 by inducing the conformational change of LATS1/2. The activated LATS1/2 phosphorylated and inactivated YAP/TAZ, preventing it from translocating into the nucleus and binding to transcription factors TEAD1–4

Fig. 3

Regulation of the Hippo pathway by upstream signals. a Five subgroups of upstream signals including cell polarity, mechanical cues, cell density, soluble factors, and stress signals are responsible for the regulation of Hippo pathway. b–f The detailed upstream signals of Hippo pathway in every subgroup

Fig. 4

The essential physiological function of Hippo pathway. The Hippo pathway effectors YAP/TAZ can take part in the modulation of multiple cell events, including proliferation, apoptosis, differentiation and growth, thereby participating in the physiological processes of embryogenesis and development, as well as tissue/organ regeneration and wound healing

Fig. 5

The summary of diseases caused by the dysregulation of the Hippo pathway. Hippo pathway dysregulation has been found to be present in a variety of organs or systems diseases and involved in the regulation of occurrence or progression of these diseases. The specific diseases are shown in boxes