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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Gindhart, Joseph G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
Schools of Arts and Sciences
United States
Zip Code
Karasmanis, Eva P; Phan, Cat-Thi; Angelis, Dimitrios et al. (2018) Polarity of Neuronal Membrane Traffic Requires Sorting of Kinesin Motor Cargo during Entry into Dendrites by a Microtubule-Associated Septin. Dev Cell 46:518-524
Spiliotis, Elias T (2018) Spatial effects?-?site-specific regulation of actin and microtubule organization by septin GTPases. J Cell Sci 131:
Angelis, Dimitrios; Spiliotis, Elias T (2016) Septin Mutations in Human Cancers. Front Cell Dev Biol 4:122
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
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
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 427:3273-3284
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; Hu, Qicong; Spiliotis, Elias T (2014) Septin functions in organ system physiology and pathology. Biol Chem 395:123-41
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

Showing the most recent 10 out of 16 publications