Calcium, an Emerging Intracellular Messenger for the Hippo Pathway Regulation

Abstract

The Hippo pathway is a conserved signaling network regulating organ development and tissue homeostasis. Dysfunction of this pathway may lead to various diseases, such as regeneration defect and cancer. Studies over the past decade have found various extracellular and intracellular signals that can regulate this pathway. Among them, calcium (Ca2+) is emerging as a potential messenger that can transduce certain signals, such as the mechanical cue, to the main signaling machinery. In this process, rearrangement of the actin cytoskeleton, such as calcium-activated actin reset (CaAR), may construct actin filaments at the cell cortex or other subcellular domains that provide a scaffold to launch Hippo pathway activators. This article will review studies demonstrating Ca2+-mediated Hippo pathway modulation and discuss its implication in understanding the role of actin cytoskeleton in regulating the Hippo pathway.

Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis

“…While the analysis of kinase activity was not performed in our study, it can be speculated that Piezo1 indirectly inhibits phosphorylation of LATS1, thereby exerting its cytoskeletal regulatory function. Alternatively, given recent studies showing that Hippo pathway in tumor may be affected by intracellular calcium levels [ 17 , 18 ], it is also possible that phosphorylation of LATS1 may be inhibited by intracellular calcium, which activates certain phosphatases. Further studies are needed to further explore these hypotheses.…”

Calmodulin activates the Hippo signaling pathway by promoting LATS1 kinase–mediated inhibitory phosphorylation of the transcriptional coactivator YAP

“…Recent evidence indicates that changes in intracellular Ca 2+ levels modulate Hippo signaling (22,48,49). Intriguingly, some studies show that Ca 2+ signaling activates Hippo, whereas others report an inhibitory effect of Ca 2+ (22). These observations indicate that the Hippo-Ca 2+ interconnection is complex and likely determined by spatial and temporal factors.…”

“…Recent evidence indicates that changes in intracellular Ca 2+ levels modulate Hippo signaling (22,48,49). Intriguingly, some studies show that Ca 2+ signaling activates Hippo, whereas others report an inhibitory effect of Ca 2+ (22).…”

“…Reports that Ca 2+ signaling modulates Hippo (22) prompted us to investigate whether the Ca 2+ -binding protein calmodulin, which regulates several signaling networks (18)(19)(20)(21), influences Hippo activation. To do so, we first assessed whether calmodulin associates with the Hippo transcriptional coactivator YAP.…”

“…Calmodulin has been documented to regulate in a Ca 2+dependent manner several major signaling pathways, including the mitogen-activated protein kinase (18,19) and PI3K/protein kinase B networks (20,21). Nevertheless, despite reports that Ca 2+ signaling influences the Hippo network (22), the possible involvement of calmodulin in modulating Hippo had not been investigated. Therefore, we tested the hypothesis that calmodulin regulates Hippo signaling.…”