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Home | Pregnancy Timeline | News Alerts |News Archive Aug 8, 2013

 

Inactivation of Par-1 restricts organ growth.

(B) Dorsal view of adult wings: wild type (normal)
(B′) Wings expressing Par-1 RNAi under the control of MS1096h.






WHO Child Growth Charts

 

 

 

Found: Par-1, a new component in a complex influencing organ growth

In the development of animals, the regulation of organ size is a long-standing puzzle. How does an organ ascertain its optimum size? What are the molecular mechanisms that stop organ growth at an appropriate point during development or regeneration? Almost a decade ago, the discovery of the Hippo signaling pathway provided an important starting point for answering these questions.

Now, a team of scientists led by Lei Zhang at the Shanghai Institute of Biochemistry & Cell Biology, Chinese Academy of Sciences, has identified a novel component of this pathway, which influences the Hippo protein's phosphorylation status and Hippo-Salvador (another key component of this pathway) association to negatively regulate Hippo kinase activity. Their findings will be published in the open access journal PLOS Biology.


The Hippo pathway regulates organ growth by inhibiting the transcription coactivator, Yorkie, through a series of phosphorylation events, thereby controlling cell numbers in a specific organ.

To initiate these phosphorylation events, Hippo kinase needs to be phosphorylated on the Thr195 site.

Without inhibition signaling from Hippo, Yorkie translocates into the nucleus, binding transcription factors and inducing specific genes promoting proliferation — while inhibiting apoptosis (cell death).


Extensive research has been focused on the study of inappropriate overgrowth induced by Yorkie activity, which is believed to be related to human cancers. However, the mechanisms that restrict Hippo kinase activity, which results in increased apoptosis and reduced tissue growth, remain unclear. In particular, the identity of the kinase that antagonizes Hippo remains unknown.

To help elucidate these mechanisms, the Zhang group performed a gain-of-function screen in Drosophila melanogaster to identify the negative regulators of the Hippo pathway. After screening more than 10,000 lines, they found that Par-1, a multifunctional serine/threonine kinase, promotes organ growth by affecting the Hippo signaling pathway.


Dr. Lei Zhang and colleagues demonstrated that Par-1 physically interacts with Hippo and its scaffold protein, Salvador.


Using biochemical approaches, they were able to show that Par-1 regulates the phosphorylation of Hippo at Ser30 and promotes the dissociation of Salvador from the Hippo-Salvador complex, eventually resulting in Salvador dephosphorylation and destabilization.

"How the activity of Hippo is regulated is fascinating to all scientists in this field. Our studies provide the first-hand evidence that, besides the well-known Thr195 autophosphorylation site, Hippo's activity can be affected by another phosphorylation site," said first author Hongling Huang.

"With this new understanding of how Par-1 regulates Hippo activity and prevents inappropriate Hippo activation, our knowledge of the Hippo signaling network has greatly expanded. As the function of Par-1 in regulating Hippo signaling is evolutionarily conserved, our studies also suggest Par-1 plays a role in carcinogenesis," added Dr. Lei Zhang. "Considering that Par-1 is a well-known polarity regulator, we'd like to focus on exploring the relationship between the Hippo pathway and the polarity components in the future."

Abstract
The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. Here, we reported the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevated Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminished Hpo target gene expression and reduced organ size. We demonstrated that par-1 functioned downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, we also found that Par-1 physically interacted with Hpo and Sav and regulated the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibited the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, we provided evidence that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, our findings identified Par-1 as a novel component of the Hpo signaling network.

Author Summary
An organism's organ size is determined by cell number, the size of each cell, and the distance between cells. All of these factors are controlled by the coordination of different cell signaling pathways and other mechanisms. The Hippo signaling pathway controls organ size by restricting the number of cells that make up the organ. Malfunction of this pathway leads to abnormal overgrowth, and is involved in a large number of human diseases and cancers. We identify here a component of the Hippo pathway, Par-1, which controls tissue growth by negatively regulating the Hippo pathway. We show that overexpression or depletion of Par-1 influences tissue growth in fruit flies via Hippo signaling. Then, by genetic and biochemical experiments, we show that Par-1 interacts with Hippo, regulating the Hippo Ser30 phosphorylation status to alter Hippo activity. In addition, we found that Par-1 regulates Hippo signaling via inhibition of the Hippo-Salvador association in a kinase-dependent fashion. We predict that Par-1 is a potential oncogene and that its regulatory role in Hippo signaling could be conserved.

Funding: This research was supported by grants from the National Basic Research Program of China (973 Program 2010CB912101, 2012CB945001, 2011CB943902, 2010CB529901, 2011CB510104), from the "Strategic Priority Research Program" of the Chinese Academy of Sciences, grant no. XDA01010406, XDA01010405, and also supported by grants from National Natural Science Foundation of China (31171394, 31171414, 30623003, 81172449), from National Key Basic Research and Development Program of China (2011CB915502) as well as Welch Foundation (I-1603) to JJ. LZ is the scholar of the Hundred Talents Program of the Chinese Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Citation: Huang H-L, Wang S, Yin M-X, Dong L, Wang C, et al. (2013) Par-1 Regulates Tissue Growth by Influencing Hippo Phosphorylation Status and Hippo- Salvador Association. PLoS Biol 11(8): e1001620. doi:10.1371/journal.pbio.1001620

Original press release: http://www.eurekalert.org/pub_releases/2013-08/plos-sdp073113.php