I’m on a YAP kick lately! This is another paper about the Hippo pathway and YAP but in relation to glucose homeostasis and cellular energy stress. In summary, the Hippo pathway is a tumor suppressor pathway. Energy stress, defects in glucose metabolism, and glucose starvation, all activate this pathway and decrease oncogenic downstream components (specifically YAP).

The implications? Metabolic regulation and glucose homeostasis are integral pieces in the puzzle that is “What causes cancer?”

Summary & Key Points:

  • The Hippo pathway is a signaling pathway that is involved in the control of tissue and organ size in the body.
  • Loss of the Hippo path components leads to tumor formation, which suggests that the Hippo path is crucial for suppressing tumors.
  • One of the major targets of the Hippo path is YAP, and YAP has recently been identified as an oncogene.
  • In cancer, you see downregulation of the Hippo path, with upregulation of YAP/TAZ.
  • Cell adhesion junction and tight junction, as well as cell-density, apparently regulates the Hippo path.
  • Aside from these mechanisms, there is an independent factor regulating the Hippo path: energy homeostasis and glucose metabolism. Energy stress, defects in glucose metabolism, and glucose starvation, all activate the Hippo path and decrease oncogenic downstream components.
  • Glucose starvation increased phosphorylation of YAP at S127 site. When glucose was added back, this phosphorylation decreased. This was transient since 2 hours later the YAP recovered.
  • Upstream kinases (LATS1 and MST1) were not affected. By using various analogs of glucose, some of which that aren’t able to undergo glycolysis, they confirmed that the glucose molecule itself was the factor involved in regulating YAP phosphorylation.
  • A 2-DG induced defect in glucose metabolism could inhibit YAP function.
  • Releasing the cell from energy stress activates YAP
  • They found indication that AMPK may directly phosphorylate YAP in response to energy stress; and likely phosphorylates the S61 site.
  • “These results indicate that energy stress may activate two parallel cellular signaling pathways, AMPK and the Hippo pathway, which phosphorylate YAP at least at the S61 and S127 sites, respectively.”
  • It is most likely that YAP transcriptional activity is suppressed by AMPK, but YAP’s degradation is not affected by AMPK: it does not increase the association with TEAD based on monitoring S61 site. However, another site, S94, may be a AMPK phosphorylation site on YAP… and mutant versions of this site show decreased association with TEAD. This implies that there may indeed be some role for AMPK in YAP degradation.
  • “The observation that energy stress regulated YAP S127 phosphorylation indicates that the Hippo pathway was also activated by energy stress.” YAP S127 phosphorylation in response to energy stress is induced by LATS kinase activation. MST kinases are not activated in response to energy stress.
  • Inducing actin depolymerization in cells released from energy stress causes an increase in YAP phosphorylation (it reversed the decrease in phosphorylation accompanying release from energy stress). Inhibition of Rho GTPase also does this. Release from energy stress increases Rho GTPase activity. Rho GTPase activity is also regulated by glucose. Energy stress may activate LATS kinases by modulating Rho GTPase activity.
  • Activated YAP promotes glycolysis.
  • YAP activity induces GLUT3 transcription. There is a TEAD binding site in the GLUT3 promoter region. Knocking down GLUT3 in YAP activated cells partially reversed glycolysis. This all suggests that GLUT3 is at least one piece of the YAP activated glycolytic pathway.
  • YAP and GLUT3 are both highly expressed in tumors as opposed to normal tissues.

Potential implications:

  • If cellular energy status regulates oncogenic pathways, with energy stress promoting non-oncogenic pathways, then may give weight to the claim that “fasting” is beneficial.
  • It also may give weight to the claim that you can “starve” cancer.
  • AMPK activators like Metformin and Berberine may be preventative for cancer.

Study drawbacks:

  • Isolated mouse embryonic fibroblasts were used, as well as genetically altered cells and mice. Thus the results need to be interpreted with caution.

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