Hippo signaling pathway

Protein MST1 PDB 2asu

Hippo signaling pathway is a signal transduction pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway is named after the Hippo protein in Drosophila melanogaster (fruit fly), where the pathway was first discovered. Its components and functions are highly conserved across different species, including humans, indicating its vital role in developmental biology and cell biology.

Overview

The Hippo signaling pathway is involved in the regulation of cell growth, cell death, and cell differentiation. It plays a critical role in maintaining tissue homeostasis and preventing tumor formation. When activated, the pathway inhibits cell proliferation and promotes apoptosis, thereby controlling organ size and suppressing cancer development.

Components

The core components of the Hippo signaling pathway include the kinases MST1 and MST2 (homologs of the Drosophila Hippo protein), the scaffold proteins SAV1 (Salvador homolog 1), the kinases LATS1 and LATS2 (large tumor suppressor homolog 1 and 2), and the adaptor proteins MOB1A and MOB1B. Downstream of these core components are the transcription co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), which when phosphorylated by the LATS kinases, are sequestered in the cytoplasm and prevented from entering the nucleus.

Function

In the absence of Hippo pathway activation, YAP and TAZ are not phosphorylated and can translocate into the nucleus where they interact with transcription factors such as TEADs (TEA domain family members) to promote the expression of genes involved in cell proliferation and survival. Thus, the Hippo pathway negatively regulates the activity of YAP and TAZ to control cell growth and apoptosis.

Regulation

The Hippo signaling pathway is regulated by various mechanisms, including cell-cell contact, mechanical stress, and G-protein coupled receptor (GPCR) signaling. Cell density, for instance, can influence the pathway's activity, with high cell density leading to pathway activation and growth inhibition. This suggests a role for the Hippo pathway in sensing and responding to changes in the microenvironment.

Role in Disease

Dysregulation of the Hippo pathway has been implicated in the development of cancer, as it can lead to unchecked cell proliferation and resistance to cell death. Mutations or altered expression of pathway components, such as YAP and TAZ, have been found in various cancers, highlighting the pathway's potential as a target for cancer therapy.

Research and Therapeutic Potential

Research into the Hippo signaling pathway continues to uncover its complex roles in development, regeneration, and disease. Targeting the pathway offers promising therapeutic potential for cancer and regenerative medicine. Inhibitors of YAP and TAZ activity, for example, are being explored as novel cancer therapeutics.