Hippo Signaling: Emerging Pathway in Stress-Related Psychiatric Disorders?

Abstract

Discovery of the Hippo pathway and its core components has made a significant impact on our progress in the understanding of organ development, tissue homeostasis, and regeneration. Upon diverse extracellular and intracellular stimuli, Hippo signaling regulates stemness, cell proliferation and apoptosis by a well-conserved signaling cascade, and disruption of these systems has been implicated in cancer as well as metabolic and neurodegenerative diseases. The central role of Hippo signaling in cell biology also results in prominent links to stress-regulated pathways. Genetic variations, epigenetically provoked upregulation of Hippo pathway members and dysregulation of cellular processes implicated in learning and memory, are linked to an increased risk of stress-related psychiatric disorders (SRPDs). In this review, we summarize recent findings, supporting the role of Hippo signaling in SRPDs by canonical and non-canonical Hippo pathway interactions.

Keywords: GPCRs; KIBRA; glucocorticoids; hippo pathway; psychophysiological stress; synaptic plasticity.

Figure 1

The Hippo Pathway and its canonical upstream regulators. The translocation of YAP and TAZ and respective translational effects of the Hippo pathway are omitted when these two factors are phosphorylated due to LAST1/2 and MST1/2 activity. Both components can be affected independently via a wide range of canonical upsream regulators. Being retained in the cytoplasm YAP and TAZ are ubiquitinated and degraded. ADHD, attention deficit hyperactivity disorder. LATS 1/2, large tumor suppressor kinase 1/2; MOB1A/MOB1B, Mps one binder kinase activator 1A/1B; MST1/2, macrophage-stimulating protein 1/2; SAV1, salvador family WW domain containing protein 1 (protein WW45); TAZ, transcriptional co-activator with PDZ-binding motif; TEAD1-4, TEA domain transcription factors 1-4; YAP, yes-associated protein.

Figure 2

KIBRA/Hippo pathway as a shunt of stressful input. In the postsynaptic button Hippo pathway is modulated with a variety of secondary messenger systems, implemented in transduction of neurontransmitters, neuropeptides, and hormones. The Hippo pathway biderectioinally interacts with KIBRA signaling. In turn, the adaptive, neuroplasticity determined by AMPAR expression (and trafficking) is promoted. AMPARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; cAMP, cyclic adenosine monophosphate; FN1, fibronectin 1; Fz, Frizzeled; GSK3, Glycogen synthase kinase 3; GPCR, G protein coupled receptors; GR, glucocorticoid receptor; KIBRA, Kidney and Brain Protein 1 (also WWC1); LATS 1/2, large tumor suppressor kinase 1/2; MOB1A/MOB1B, Mps one binder kinase activator 1A/1B; MST1/2, macrophage-stimulating protein 1/2; PICK1, protein interacting with C-kinase 1; PKA, protein kinase A; PKC, protein kinase C; Rho GTPase, Rho guanosine-5′-triphosphatase; SAV1, salvador family WW domain containing protein 1 (protein WW45); TAZ, transcriptional co-activator with PDZ-binding motif; YAP, yes-associated protein.