Par-1 Regulates Tissue Growth by Influencing Hippo Phosphorylation Status and Hippo-Salvador Association

Huang, Heng; Wang, Shimin; Yin, Meng Xin; Dong, Liang; Wang, Chao; Wu, Wei; Lu, Yi; Mao, Feng; Dai, Chuan-Yang; Guo, Xiaohong; Li, Li; Zhao, Bin; Zhou, Zhaocai; Ji, Hongbin; Jen, Jin; Zhao, Yun; Liu, Xin‐Yuan; Zhang, Lei

doi:10.1371/journal.pbio.1001620

Cited by 58 publications

(57 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1B). In Drosophila, MARK ortholog Par-1 negatively regulates the activity of hpo kinase, and overexpression of human MARK4 inhibits the Hippo pathway in HEK293T cells (Huang et al 2013). To examine the role of MARK3 in Hippo pathway regulation, we overexpressed MARK3 in HEK293T cells.…”

Section: Mark3 Inhibits the Hippo Signaling Pathwaymentioning

confidence: 99%

“…Drosophila Par-1 negatively regulates the activity of Hpo kinase by promoting inhibitory hyperphosphorylation of Hpo (Huang et al 2013). This hyperphosphorylation is distinct from specific phosphorylation of Hpo/ MST1/2 at the kinase activation loop, which, in contrast, marks kinase activation.…”

Section: Dlg5 Links Hippo and Polarity Protein Networkmentioning

confidence: 99%

“…This hyperphosphorylation is distinct from specific phosphorylation of Hpo/ MST1/2 at the kinase activation loop, which, in contrast, marks kinase activation. In mammals, the Par-1 homolog MARK4 promotes YAP/TAZ activity and induces hyperphosphorylation of MST2, although whether this hyperphosphorylation regulates MST2 activity is not yet known (Huang et al 2013).…”

Section: Dlg5 Links Hippo and Polarity Protein Networkmentioning

confidence: 99%

See 2 more Smart Citations

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

et al. 2016

View full text Add to dashboard Cite

Disruption of apical-basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5 −/− tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz. Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms.

show abstract

Section: Mark3 Inhibits the Hippo Signaling Pathwaymentioning

confidence: 99%

Section: Dlg5 Links Hippo and Polarity Protein Networkmentioning

confidence: 99%

Section: Dlg5 Links Hippo and Polarity Protein Networkmentioning

confidence: 99%

See 1 more Smart Citation

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

et al. 2016

View full text Add to dashboard Cite

show abstract

“…LKB1 has also been reported to regulate YAP through an MST/LATS-independent manner [77]. In addition, MARKs have also been reported to be YAP activators in both Drosophila and mammalian cells [78].…”

Section: Yap Is Regulated By Protein-protein Interactionsmentioning

confidence: 99%

The regulation and function of YAP transcription co-activator

Zhu

Zhao

2015

ABBS

Self Cite

110

View full text Add to dashboard Cite

The Hippo pathway was initially identified in Drosophila by genetic mosaic screens for tumor suppressor genes. Researches indicated that the Hippo pathway is a key regulator of organ size and is conserved during evolution. Furthermore, studies of mouse models and clinical samples demonstrated the importance of Hippo pathway dysregulation in human cancer development. In addition, the Hippo pathway contributes to progenitor cell and stem cell self-renewal and is thus involved in tissue regeneration. In the Hippo pathway, MST1/2 kinases together with the adaptor protein SAV phosphorylate LATS1/2 kinases. Interaction with an adaptor protein MOB is also important for LATS1/2 activation. Activated LATS1/2 in turn phosphorylate and inhibit Yes-associated protein (YAP). YAP is a key downstream effector of the Hippo pathway, and is a transcriptional co-activator that mainly interacts with TEAD family transcription factors to promote gene expression. Alteration of gene expression by YAP leads to cell proliferation, apoptosis evasion, and also stem cell amplification. In this review, we mainly focus on YAP, discussing its regulation and mechanisms of action in the context of organ size control, tissue regeneration and tumorigenesis.

show abstract

“…A CK2 point mutation (K66M) was generated by PCR-based site-directed mutagenesis and verified by DNA sequencing, and all of these cDNA fragments were cloned into the pUAST vector. Other stocks used in this study were described previously including wts (27,31). All flies and crosses were kept at 25°C unless special indication.…”

Section: Methodsmentioning

confidence: 99%

Par-1 Regulates Tissue Growth by Influencing Hippo Phosphorylation Status and Hippo-Salvador Association

Abstract: Par-1 regulates the Hippo signaling pathway in Drosophila melanogaster by modifying the phosphorylation status of Hippo and also by inhibiting the interaction of Hippo and Salvador.

Cited by 58 publications

References 62 publications

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

The regulation and function of YAP transcription co-activator

Drosophila Casein Kinase 2 (CK2) Promotes Warts Protein to Suppress Yorkie Protein Activity for Growth Control

Contact Info

Product

Resources

About