Hippo Signaling Regulates Differentiation and Maintenance in the Exocrine Pancreas

Gao, Tao; Zhou, Dawang; Yang, Chenghua; Singh, Tarjinder; Penzo–Méndez, Alfredo; Maddipati, Ravikanth; Tzatsos, Alexandros; Bardeesy, Nabeel; Avruch, Joseph; Stanger, Ben Z.

doi:10.1053/j.gastro.2013.02.037

Cited by 136 publications

(167 citation statements)

References 23 publications

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“…Modulation of Hippo signaling has frequently been reported to result in alterations of Notch target gene expression. For example, genetic deletion of Mst1/2 in pancreatic epithelium resulted in increased Yap expression and a robust increase in Hes1 expression (Gao et al, 2013). Yap overexpression in hepatocytes caused upregulation of Notch1/2, Jagged1, Hes1 and the Notch target Sox9 (Yimlamai et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Given the diversity and breadth of cellular contexts in which Notch and Hippo signaling function in development and disease, it is not surprising that these two signaling pathways frequently intersect Heallen et al, 2011;von Gise et al, 2012;Afelik and Jensen, 2013;Gao et al, 2013;Li et al, 2009;Makita et al, 2008). For example, hepatocyte-specific Yap overexpression leads to an upregulation of Notch1, Notch2, Jagged1 (Jag1) and the Notch target gene Hes1 (Yimlamai et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest

et al. 2015

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Notch signaling has well defined roles in the assembly of arterial walls and in the development of the endothelium and smooth muscle of the vasculature. Hippo signaling regulates cellular growth in many tissues, and contributes to regulation of organ size, in addition to other functions. Here, we show that the Notch and Hippo pathways converge to regulate smooth muscle differentiation of neural crest, which is critical for normal development of the aortic arch arteries and cranial vasculature during embryonic development. Neural crest specific deletion of the Hippo effectors Yap and Taz produces neural crest precursors that migrate normally, but fail to produce vascular smooth muscle, and Notch target genes such as Jagged1 fail to activate normally. We show that Yap is normally recruited to a tissue-specific Jagged1 enhancer by directly interacting with the Notch intracellular domain (NICD). The Yap-NICD complex is recruited to chromatin by the DNA-binding protein Rbp-J in a Tead-independent fashion. Thus, Hippo signaling can modulate Notch signaling outputs, and components of the Hippo and Notch pathways physically interact. Convergence of Hippo and Notch pathways by the mechanisms described here may be relevant to the function of these signaling cascades in many tissues and in diseases such as cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest

et al. 2015

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“…Recent work has shown that changes in YAP localization are essential for proper pancreas development (Gao et al, 2013;George et al, 2012). Analyses of pancreas-specific Mst1/2 knockout mice have revealed severe developmental defects that correlate with increased nuclear hypophosphorylated YAP (Gao et al, 2013;George et al, 2012).…”

Section: Pancreasmentioning

confidence: 99%

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

2014

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Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.

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“…[76][77][78] The involvement of the Hippo/MST2 pathway in epithelial behavior and downstream processes were recently reviewed. 79 MST2 itself and its closest isoform MST1 were shown to be crucial for 1,25-dihydroxyvitamin D 3 -mediated monocytic differentiation of myeloid leukemia HL60 cells, 42 control the downstream kinase YAP to control pancreatic acinar differentiation mice, 80 regulate trophoblast differentiation via the transcription factor Mash2 in the placenta, 81 and are required for embryonic stem cell differentiation. 82 In addition, MST1/2 play a role in differentiation of hematopoietc and endothelial progenitor cells in Xenopus, 83 and MST1 was identified as a crucial caspase-3 effector in myoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

et al. 2016

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A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the MEK-ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. We recently identified A-Raf as a potent inhibitor of the proapoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities including head and neck, colon, and breast. Independent of kinase activity, A-Raf binds to MST2 thereby efficiently inhibiting apoptosis. Here, we show that the interaction of A-Raf with the MST2 pathway is regulated by subcellular compartmentalization. Although in proliferating normal cells and tumor cells A-Raf localizes to the mitochondria, differentiated non-carcinogenic cells of head and neck epithelia, which express A-Raf at the plasma membrane. The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis. Physiologically, A-Raf re-localizes to the plasma membrane upon epithelial differentiation in vivo. This re-distribution is regulated by the scaffold protein kinase suppressor of Ras 2 (KSR2). Downregulation of KSR2 during mammary epithelial cell differentiation or siRNA-mediated knockdown re-localizes A-Raf to the plasma membrane causing the release of MST2. By using the MCF7 cell differentiation system, we could demonstrate that overexpression of A-Raf in MCF7 cells, which induces differentiation. Our findings offer a new paradigm to understand how differential localization of Raf complexes affects diverse signaling functions in normal cells and carcinomas. A-Raf is a member of the Raf family of serine-threonine protein kinases, which comprises A-Raf, B-Raf, and Raf-1. Raf kinases are at the apex of the three-tiered Raf/MEK/ extracellular signal-regulated kinase (ERK) (mitogen-activated protein kinase (MAPK)) pathway regulating fundamental cellular functions, including differentiation, transformation, apoptosis, proliferation, and metabolism. 1,2 Activation of Ras GTPases at the cell membrane initiates Raf kinase activation and sequential phosphorylation and activation of the serinethreonine kinases MEK1/2 and ERK1/2. 3,4 In comparison to Raf-1 and B-Raf, A-Raf is only weakly activated by oncogenic H-Ras and Src 5 and is a poor MEK kinase, 5-8 which is due to unique non-conserved amino acid substitutions in the N-region. 9 Only recently, the first somatic oncogenic mutations of A-Raf were identified in lung adenocarcinomas 10 and Langerhans cell histiocytosis. 11,12 We recently showed that A-Raf and Raf-1, independent of their kinase activity, bind the proapoptotic mammalian sterile 20-like kinase (MST2) thereby suppressing MST2 activation and MST2-induced apoptosis. 13-17 MST2 employs several mechanisms to induce apoptosis including the transcriptional induction of PUMA, 14 a BH3 domain protein that causes mitochondrial depolarization and subsequent cell death. 18 Although Raf-1 counteracts MS...

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Hippo Signaling Regulates Differentiation and Maintenance in the Exocrine Pancreas

Cited by 136 publications

References 23 publications

Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest

Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

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