The microtubule cytoskeleton provides a structural framework for the transport and positioning of membrane organelles and macromolecules, and is essential for cell division, cell motility and cell signaling. Disruption of microtubule-dependent transport underlies the pathogenesis and progression of cancer and neurodegeneration. Understanding the molecular mechanisms that control MT-dependent motility and MT organization is of paramount significance for the development of MT-based therapeutic interventions, many of which are being clinically applied. Recently, we discovered that a novel family of GTPases termed septins is essential for the microtubule-dependent transport of chromosomes and membrane vesicles. Septins are linked to a diversity of cancers and neurodegenerative diseases including Alzheimer's and Parkinson's. The long-term goal of our research is to understand how septins function in microtubule-dependent motility. We hypothesize that septins selectively modulate the interaction of microtubules with motors and microtubule-associated proteins (MAPs). Here, we will determine the molecular mechanism by which septins interact with microtubules. Importantly, we will test how septins influence the microtubule binding of specific motors and MAPs. We will use this knowledge to elucidate septin roles in the directionality and/or velocity of membrane traffic in live epithelia and neurons. Because the directionality of intracellular transport is influenced by the stability and orientation of individual microtubule tracks, we will examine how septins control the spatial organization and stability of microtubules. Our studies will provide new insights into the regulation of microtubule-dependent transport, and generate a model for the design of septin-based therapeutics (e.g., inhibitory peptides), which can be used as an alternative to microtubule-targeting agents.
We have identified a new family of proteins, which regulate the movement of membranous organelles and chromosomes in cells. Because these molecules are abnormally expressed in neurodegenerative diseases and cancer, we are interested in understanding: 1) how they work, 2) how they contribute to disease, and 3) how we can manipulate them to design new therapies against cancer and neurodegenerative diseases such as Alzheimer's and Parkinson's.
|Dolat, Lee; Spiliotis, Elias T (2016) Septins promote macropinosome maturation and traffic to the lysosome by facilitating membrane fusion. J Cell Biol 214:517-27|
|Bai, Xiaobo; Karasmanis, Eva P; Spiliotis, Elias T (2016) Septin 9 interacts with kinesin KIF17 and interferes with the mechanism of NMDA receptor cargo binding and transport. Mol Biol Cell 27:897-906|
|Spiliotis, E T; Karasmanis, E P; Dolat, L (2016) Fluorescence microscopy of actin- and microtubule-associated septins in mammalian cells. Methods Cell Biol 136:243-68|
|Angelis, Dimitrios; Spiliotis, Elias T (2016) Septin Mutations in Human Cancers. Front Cell Dev Biol 4:122|
|Smith, Clayton; Dolat, Lee; Angelis, Dimitrios et al. (2015) Septin 9 Exhibits Polymorphic Binding to F-Actin and Inhibits Myosin and Cofilin Activity. J Mol Biol 427:3273-84|
|Dolat, Lee; Hu, Qicong; Spiliotis, Elias T (2014) Septin functions in organ system physiology and pathology. Biol Chem 395:123-41|
|Mostowy, Serge; Bi, Erfei; Fuchtbauer, Ernst-Martin et al. (2014) Highlight: the 5th International Workshop on Septin Biology. Biol Chem 395:119-21|
|Angelis, Dimitrios; Karasmanis, Eva Pauline; Bai, Xiaobo et al. (2014) In silico docking of forchlorfenuron (FCF) to septins suggests that FCF interferes with GTP binding. PLoS One 9:e96390|
|Dolat, Lee; Hunyara, John L; Bowen, Jonathan R et al. (2014) Septins promote stress fiber-mediated maturation of focal adhesions and renal epithelial motility. J Cell Biol 207:225-35|
|Cui, Cheng; Chatterjee, Bishwanath; Lozito, Thomas P et al. (2013) Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton. PLoS Biol 11:e1001720|
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