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Getting to the Core of the Problem - New Research Delves into the Role of MOB1 in the Hippo Signalling Pathway

July 07, 2017

 

Regulation of Protein Interactions by Mps One Binder (MOB1) Phosphorylation and MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway

By Meghan Krizus

  Using x-ray crystallography, the research team was able to determine the structure of the MOB1 protein, including the sites at which it binds with specific kinases.
 

Using x-ray crystallography, the research team was able to determine the structure of the MOB1 protein, including the sites at which it binds with specific kinases.

Understanding the complex cellular pathways involved in cancer is a critical aspect in understanding the disease itself. Moreover, studying these pathways may also provide insights for development of new treatments targeted at disrupting aspects of pathways that are disrupted in cancer.

Two complementary, recent publications from research teams at the LTRI accomplish just this 1., 2.. The result of a collaboration between the Sicheri and Gingras labs, the publications’ combined body of work focuses upon a protein called MOB1. This work takes an in-depth approach into studying MOB1’s influence on the Hippo pathway, a biochemical regulatory system that has been implicated in suppressing tumour growth.

“Our labs came together to try to understand the core of the Hippo pathway,” explains author Shawn Xiong. In these back-to-back publications, researchers explored how MOB1 phosphorylation (the process by which a phosphate is added to a protein) is involved in its interactions with several families of protein kinases (enzymes that catalyze the phosphorylation of proteins). Building upon an understanding of MOB1’s interactions with these kinases, the team examined the mechanics of how MOB1 works within the Hippo pathway, including investigating the structure, function, and affinity of MOB1’s various binding sites.

According to Xiong, two methods were particularly important to the success of this study. The first, he says, was x-ray crystallography. In this method, crystallized versions of the molecule of interest are placed in an x-ray beam to create a distinct diffraction pattern. This pattern then can be mathematically translated to reveal the precise chemical structure of a molecule. Here, Xiong and his colleagues used x-ray crystallography to visualize MOB1’s atomic structure, allowing them to study how this structure related to the protein’s affinity for specific components of the Hippo pathway and, in turn, validating the compelling evidence provided by previous in vitro studies.

Xiong also points to “interactomics,” the study of the interactome (a term referring to all the interactions between molecules within a cell), as being essential to the group’s findings. Xiong and his colleagues demonstrated that introducing mutated versions of the MOB1 protein into cells can drastically modify the interactome of the Hippo pathway, complementing the publications’ structural biological evidence with protein:protein interaction evidence.

This detailed study of MOB1’s role within the Hippo pathway is important to cancer research. The Hippo pathway, so named for the discovery that mutations in this pathway causes abnormal cell proliferation and organ growth in the fruit fly Drosophila melanogaster, is highly conserved and exists in mammals, including humans. Because of Hippo’s role in regulating organ size via its control of cell proliferation and apoptosis (programmed cell death), this pathway is a target for studies on abnormal growth, a hallmark of cancer.

Additionally, this research may have significance to drug discovery given that it has elucidated the role and affinity of MOB1’s protein-binding domains. With an understanding of the structure and affinity of MOB1 binding sites, cancer-fighting drugs could be designed to interact with the Hippo pathway via disrupting specific regions on MOB1.

These discoveries provide an important step forward in understanding MOB-family proteins and their role in signalling pathways likes Hippo, but according to Xiong, this is just the beginning. In his own words, this research opens the door to many more discoveries, as “in humans, there are seven [MOB proteins] in total, and we investigated only one…so what are all the other six doing? We know nothing about them!”
 

References:


  1. MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway.
    Couzens AL, Xiong S, Knight JDR, Mao DY, Guettler S, Picaud S, Kurinov I, Filippakopoulos P, Sicheri F, Gingras AC.
    Mol Cell Proteomics. 2017 Jun;16(6):1098-1110. doi: 10.1074/mcp.M116.065490. Epub 2017 Apr 3.
    PMID: 28373298

  2. Regulation of Protein Interactions by Mps One Binder (MOB1) Phosphorylation.
    Xiong S, Couzens AL, Kean MJ, Mao DY, Guettler S, Kurinov I, Gingras AC, Sicheri F.
    Mol Cell Proteomics. 2017 Jun;16(6):1111-1125. doi: 10.1074/mcp.M117.068130. Epub 2017 Apr 3.
    PMID: 28373297



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