The Hippo pathway is controlled by Angiotensin II signaling and its reactivation induces apoptosis in podocytes.
The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that either activate or inactivate the Hippo pathway via the large tumor suppressor kinase (LATS) and its substrate, the co-transcription factor Yes-associated protein (YAP). In this study, we focused on the Angiotensin II type 1 receptor (AT1R), which belongs to the GPCR family and has an essential role in the control of blood pressure and water homeostasis. We found that Angiotensin II (Ang II) inactivates the pathway by decreasing the activity of LATS kinase; therefore, leading to an enhanced nuclear shuttling of unphosphorylated YAP in HEK293T cells. This shuttling of YAP is actin-dependent as disruption of the actin cytoskeleton inhibited dephosphorylation of LATS and YAP. Interestingly, in contrast to HEK293T cells, podocytes, which are a crucial component of the glomerular filtration barrier, display a predominant nuclear YAP localization in vivo and in vitro. Moreover, stimulation with Ang II did not alter Hippo pathway activity in podocytes, which show a deactivated pathway. Reactivation of the LATS kinase activity in podocytes resulted in an increased cytoplasmic YAP localization accompanied by a strong induction of apoptosis. Thus, our work indicates that the control of LATS activation and subsequent YAP localization is important for podocyte homeostasis and survival.
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
D O
DO
Wennmann
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
B
B
Vollenbröker
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
A K
AK
Eckart
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
J
J
Bonse
Institute of Physiology I, Westfaelische Wilhelms-University, Muenster, Germany.
F
F
Erdmann
Analytical Chemistry NC4/72, Biomolecular Mass Spectrometry/Proteincenter, Ruhr-University Bochum, Muenster, Germany.
D A
DA
Wolters
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
L K
LK
Schenk
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
U
U
Schulze
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
J
J
Kremerskothen
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
T
T
Weide
Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
H
H
Pavenstädt
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D002470:Cell Survival; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D044140:Receptor, Angiotensin, Type 1; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000804:Angiotensin II; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases