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Currently, my lab addresses the following questions:

How does the pseudophophatase MK-STYX inhibit stress granule formation?

Environmental cues such as heat shock, UV irradiation, hypoxia, and oxidative stress initiate many eukaryotic cellular responses, including protective responses to ensure their survival.  One of the most rapid of these responses is to prevent mRNA translation to into protein to allow cells to adapt to stress. This stalled mRNA is sequestered to specific cytosolic compartments known as stress granule. Stress granules represent a complex assemblage of translational initiation factors, proteins involved in translational control, the microtubule array, and chaperone proteins such as G3BP-1 (Ras-GTPase-activating protein Src homology 3 domain-binding protein-1). We have shown that MK-STYX binds G3BP-1 and inhibit stress granule formation. However, how MK-STYX accomplishes this inhibition is unclear. Thus, we seek to elucidate the mechanism required by MK-STYX to inhibit stress granule formation? Understanding this mechanism will proved insight into the role MK-STYX plays as a regulator of mRNA stability and in the dynamics of stress granule formation.



What role(s) does MK-STYX play in neuronal differentiation?

The role of the MAPK (Mitogen-activated protein kinase) signal pathway in neuronal development has received increasing attention in the past several years. Environmental stimuli such as neurotrophins, growth signals, and stress activate receptor tyrosine kinases that are responsible for initiating the phosphorylation cascade required to trigger the MAPK cascade. MAPKs are abundantly expressed in neurons in the central nervous system, thus it is not surprising that a malfunction in this signaling cascade would lead to neurological disorders.  Intriguingly, some neurological disorders are caused by hyperphosphorylation, whereas others are caused by the inhibition of MAPK phosphorylation. Despite compelling evidence that MAPKs are significant regulators in neuronal development, how the MAPK signaling pathway is maintained and modulated remains elusive. My lab investigates the role the pseudophosphatase MK-STYX plays in neuronal development and in modulating the MAPK cascade.

What involvement does MK-STYX has in protein: protein interactions?

Although the critical cysteine required for phosphatase activity is missing in MK-STYX, MK-STYX still binds targeted proteins such as G3BP-1. Many pseuodophosphatases such as the myotubularins have been shown to interact with their active homologs creating psuedophosphatase:phosphatase interactions. MK-STYX is not only a pseudophosphatase, but also consists of a rhodanese domain that may serve as a docking domain for proteins such as MAPKs. Understanding the MK-STYX’s protein interactions may lead to the functional importance of pseudophosphatases. My lab will begin to identify interesting binding partners of MK-STYX through proteomics.

Addressing these questions may provide substantial evidence for the advantage of pseudophosphatases over active enzymes in modulating signaling pathways, and will provide a platform for better understanding their misregulation in diseases such as cancers and neurological disorders, in which some pseudophosphatases are highly expressed.