Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer

Abstract

Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment.

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…YAP is thought to promote cell proliferation and differentiation by regulating the expression of its target genes in various cell types, including IECs (37,38). Indeed, YAP was previously shown to be predominantly expressed in crypts of the small intestine (45).…”

“…Activation of the Hippo signaling pathway upstream of YAP results in the degradation of YAP in the cytoplasm in a manner dependent on the ubiquitin-proteasome system. Conversely, inactivation of the Hippo pathway prevents the degradation of YAP, which then translocates to the nucleus and initiates transcription of its target genes (37). The amount of YAP in isolated crypts of the ileum was markedly greater for those from Csk CKO mice than for those from control mice (Fig.…”

“…YAP and TAZ function as transcriptional coactivators in the Hippo signaling pathway, with YAP being thought to promote cell proliferation and differentiation by regulating the expression of its target genes in various cell types, including IECs (37,38). Activation of the Hippo signaling pathway upstream of YAP results in the degradation of YAP in the cytoplasm in a manner dependent on the ubiquitin-proteasome system.…”

“…The phosphorylation of YAP at Ser 381 by Lats is thought to promote the degradation of YAP in the cytoplasm and thereby to regulate the amount of this protein in cells (37,39). In contrast, phosphorylation of YAP at Ser 127 by Lats promotes the association of YAP with 14-3-3 and thereby prevents the nuclear translocation of YAP (37,40). The level of YAP phosphorylation at both Ser 127 and Ser 381 was markedly reduced in crypts of Csk CKO mice compared with those of control mice (Fig.…”

Des insulines pour orchestrer la croissance

“…Des niveaux transcriptionnels de dilp8 en condition normale de croissance des tissus [31]. La voie Hippo/Yki est conservée au cours de l'évo-lution et joue un rôle clé dans le contrôle de la taille des organes en couplant les paramètres biomécaniques des tissus (densité cellulaire et contraintes physiques) avec la croissance et la prolifération cellulaire [32,33] (➜). Le dérèglement de la voie Hippo est impliqué dans de nombreux cancers humains [5].…”