Hippo signaling cascade ; GO:0035329

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HIPPO SIGNALING OVERVIEW

For a diagram, see Figure 2 in PMID 21138973 [2]


  • HIPPO = MST1, MST2
  • SAV = WW45
  • YKI = YAP/TAZ

1. The Hippo pathway consists of a core kinase cascade in which Hpo phosphorylates and activates the protein kinase Warts (Wts).

2. Two proteins are known to facilitate the activation of Wts: Salvador (Sav) and Mob as tumor suppressor (Mats).

    • Hpo can bind to and phosphorylate Sav, which may function as a scaffold protein
    • Hpo can also phosphorylate and activate Mats (MOBKL1A/B in mammals), which allows Mats to associate with and strengthen the kinase activity of Wts.

3. Activated Wts can then go on to phosphorylate and INACTIVATE the transcriptional coactivator Yorkie (Yki).

4. Yki is unable to bind DNA by itself. In its active state, Yki binds to the transcription factor Scalloped (Sd), and the Yki-Sd complex becomes localized to the nucleus. This allows for the expression of several genes that promote organ growth. Thus, the INACTIVATION of Yki by Wts inhibits growth through the transcriptional repression of these pro-growth regulators. By phosphorylating Yki at serine 168, Wts promotes the association of Yki with 14-3-3 proteins, which help to anchor Yki in the cytoplasm and prevent its transport to the nucleus.

UPSTREAM REGULATORS OF HIPPO SIGNALING

A number of cell surface receptors may feed-into/regulate the Hippo cascade, including GPCRs, Wnt signaling, TGF-beta signaling and the receptor, FAT:

See PMID 21084559 for hippo signaling dowstream of Wnt, TGF-beta etc

See PMID 22901800 for hippo signaling downstream of GPCRs.


ACTIVATION OF HIPPO SIGNALING BY FAT

  1. FAT (a receptor for the ligand Dachsous, see figure at the top of this wiki page) acts upstream of Hippo. Fat activates Hpo through the apical protein Expanded (FDM6 in mammals).
  2. Ex interacts with two other apically-localized proteins, Kibra (KIBRA in mammals) and Merlin (Mer; NF2 in mammals), to form the Kibra-Ex-Mer (KEM) complex.
  3. The KEM complex physically interacts with the Hpo kinase cascade, thereby localizing the core kinase cacade to the plasma membrane for activation.


GENE PRODUCTS

Taken from Wikipedia

HIPPO SUMMARY.png


QUESTIONS

The cascade STARTS with the action of the kinase HIPPO. Where does the cascade end?

Are Yki/YAP/TAZ participants in the cascade? (they are transcriptional regulators that are INACTIVATED by hippo).

Are the InterPro mappings correct? Should TFs that partner with YKI (ie. are the TARGETS/OUTPUT of the pathway) be annotated to the pathway itself??


HIPPO SIGNALING GO TERMS

[Term]
id: GO:0035329
name: hippo signaling cascade
namespace: biological_process
def: "The series of molecular signals mediated by the serine/threonine kinase Hippo or one of its orthologs. In Drosophila, Hippo in complex with the scaffold protein Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates  and inactivates the Yorkie (Yki) transcriptional activator. The core fly components hippo, sav, wts and mats are conserved in mammals as STK4/3 (MST1/2), SAV1/WW45, LATS1/2 and MOB1." [PMID:17318211, PMID:18328423]
synonym: "Salvador-Warts-Hippo signaling pathway" NARROW []
synonym: "SWH pathway" NARROW []

InterPro X-refs

http://www.ebi.ac.uk/interpro/entry/IPR016361 Transcriptional enhancer factor (IPR016361)

http://www.ebi.ac.uk/interpro/entry/IPR027253 Transcriptional enhancer factor TEF-5 (TEAD3) (IPR027253)

TEAD/TEF proteins are DNA-binding transcription factor that partners with Yki to mediate the transcriptional output of the Hpo growth-regulatory pathway [PMID 18258486, PMID 18331708]

QUESTION: ARE THESE X-REFS CORRECT?Bold text


REFERENCES

Wikipedia

Cell signal

SnapShot: The hippo signaling pathway [PMID 21529719]

Hippo signaling: growth control and beyond [PMID 21138973]

Hippo signaling goes long range [PMID 22901800]