Cell migration is promoted by the alternating formation and disassembly of focal adhesions (FAs);our long-term goal is to understand the mechanisms that govern these dynamic events. In FA formation, multiple adhesion molecules are concentrated in a small area in which complex protein interactions are highly specific, although some of the binding affinities are relatively weak. Because of the relatively high protein concentration at the FA locus, binding affinity plays a critical role, and phosphorylation-mediated changes in binding affinity can completely alter the balance of interactions within the complex network. Therefore, to elucidate the mechanism that regulates the formation and disassembly of focal adhesions, we must understand in detail the structural and biophysical interactions within FAs and their binding partners and determine how phosphorylation affects these interactions;this is the focus of the project. Specifically, we will study paxillin family proteins and their biding partners in FAs. Paxillin and its related proteins are key players in FAs;as scaffold proteins, they use their N-terminal LD motifs to interact with other FA molecules. One major group of LD binding partners comprises the focal adhesion targeting (FAT) domain of FAK and the FAT-like domains of other FA proteins. Although the FAT-like domains have similar structures, their interactions with the LD motifs of paxillin family proteins differ in many ways. These differences offer an opportune starting point to dissect the dynamics of the complex interactions in FA formation and disassembly. This study will also aid in the design of inhibitors that target specifi binding events in FAs in order to mediate FA dynamics.
Cell migration is promoted by the alternating formation and disassembly of focal adhesions;our long-term goal is to understand the mechanisms that govern these dynamic events. Inappropriate regulations of focal adhesion dynamics have been implicated in cancer and other human diseases. Therefore, the knowledge obtained from the studies in the current project will not only help to explain the fundamental chemical nature of the complex molecular interplay in focal adhesions but may also lead to the development of therapeutic agents that target pathogenic abnormalities in FA signaling.
|Keller, Kate E; Bhattacharya, Sanjoy K; Borrás, Theresa et al. (2018) Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res 171:164-173|
|Zhang, Chi; Miller, Darcie J; Guibao, Cristina D et al. (2017) Structural and functional insights into the interaction between the Cas family scaffolding protein p130Cas and the focal adhesion-associated protein paxillin. J Biol Chem 292:18281-18289|
|Qi, Jing; Lee, Ho-Jin; Saquet, Audrey et al. (2017) Autoinhibition of Dishevelled protein regulated by its extreme C terminus plays a distinct role in Wnt/?-catenin and Wnt/planar cell polarity (PCP) signaling pathways. J Biol Chem 292:5898-5908|
|Ahadome, Sarah D; Zhang, Chi; Tannous, Elizabeth et al. (2017) Small-molecule inhibition of Wnt signaling abrogates dexamethasone-induced phenotype of primary human trabecular meshwork cells. Exp Cell Res 357:116-123|
|Bao, Ju; Marathe, Bindumadhav; Govorkova, Elena A et al. (2016) Drug Repurposing Identifies Inhibitors of Oseltamivir-Resistant Influenza Viruses. Angew Chem Int Ed Engl 55:3438-41|
|Young, Alejandra; Dandekar, Uma; Pan, Calvin et al. (2016) GNAI3: Another Candidate Gene to Screen in Persons with Ocular Albinism. PLoS One 11:e0162273|
|Vanarotti, Murugendra S; Finkelstein, David B; Guibao, Cristina D et al. (2016) Structural Basis for the Interaction between Pyk2-FAT Domain and Leupaxin LD Repeats. Biochemistry 55:1332-45|
|Lee, Ho-Jin; Bao, Ju; Miller, Ami et al. (2015) Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled. J Biol Chem 290:30596-606|
|Vanarotti, Murugendra S; Miller, Darcie J; Guibao, Cristina D et al. (2014) Structural and mechanistic insights into the interaction between Pyk2 and paxillin LD motifs. J Mol Biol 426:3985-4001|
|Brown, Nicholas G; Watson, Edmond R; Weissmann, Florian et al. (2014) Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly. Mol Cell 56:246-260|
Showing the most recent 10 out of 13 publications