These cells were scratch-wounded followed by fixation 12-hours post-wounding. Tubulin (Green) and alpha-mannosidase II (Red) were labeled to note cell polarization and Golgi orientation. Cells expressing paxillin lacking LD4 are unable to reorient the Golgi towards the wound edge. From the lab of Christopher Turner, PhD.
Physiological functions of myosin motors and their roles in diabetic kidney disease and cancer
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We are interested in the roles of fundamental cell biological processes such as cell motility, cell adhesion, and membrane trafficking in the pathogenesis of human diseases, such as cancer, diabetes, and chronic kidney disease.
Studies in the lab are focused primarily on intracellular functions of myosins, molecular motors that use the energy of ATP hydrolysis to transport various cargo along actin filaments. Myosins form a large protein superfamily, with many cell types expressing multiple myosin isoforms. Myosin motors have been implicated in many important physiological processes including cell migration and adhesion, cell signaling, organelle transport, and cell division. Mutations in myosin genes have been linked to a variety of human diseases, including neurological disorders, hearing loss, kidney disease, and cancer.
Our research focuses primarily on the physiological roles of a mammalian myosin called myosin 1e. There are two major directions of research in the lab.
(1) Identification of binding partners and intracellular functions of myosin 1e.
We have recently discovered that myosin 1e interacts with clathrin-coated vesicles and is involved in clathrin-dependent endocytosis. The next challenge will be to determine which membrane receptors are internalized via myosin 1e-dependent pathways, how myosin 1e contributes to clathrin-coated vesicle formation and internalization, and how myosin 1e activity and localization are regulated during endocytosis. These studies are performed primarily in cultured mammalian cell lines, in which myosin 1e expression and activity can be manipulated using RNA interference and expression of dominant-negative constructs. In order to follow changes in myosin 1e localization during endocytosis, we use fluorescently tagged protein constructs that can be observed using live cell imaging.
(2) Analysis of myosin 1e functions at the whole-animal level.
We have recently created a knockout mouse that lacks myosin 1e, and are using this mouse model to study the roles of myosin 1e in various tissues and organs. Initial characterization of the KO mice revealed that these animals exhibit a severe defect in renal filtration, which is caused by the structural abnormalities in renal glomeruli, the primary site of renal filtration. The defects in glomerular filtration and organization observed in myosin 1e-null mice are similar to those found in inherited glomerular diseases in humans. In addition to studies of renal functions, we are also analyzing other tissues and cell types in myosin 1e-null mice that may require myosin 1e activity for normal functions. Cell types under study include osteoclasts (cells involved in bone remodeling), macrophages, and neurons.
Work in the lab is supported by grants from the American Diabetes Association and the Nephcure Foundation.
M.Krendel, S.V.Kim, T. Willinger, T. Wang, M. Kashgarian, R.A. Flavell, and M.S. Mooseker. Disruption of myosin 1e promotes podocyte injury. Journal of American Society of Nephrology, 20:86-94, 2009.
Krendel M, Osterweil EK, Mooseker MS. Myosin 1E interacts with synaptojanin-1 and dynamin and is involved in endocytosis. FEBS Letters. 2007 Feb 20;581(4):644-50.
Krendel M, Mooseker MS. Myosins: tails (and heads) of functional diversity. Physiology. 2005 Aug;20:239-51.
Krendel M, Zenke FT, Bokoch GM. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nature Cell Biology. 2002 Apr;4(4):294-301.
Krendel M, Gloushankova NA, Bonder EM, Feder HH, Vasiliev JM, Gelfand IM. Myosin-dependent contractile activity of the actin cytoskeleton modulates the spatial organization of cell-cell contacts in cultured epitheliocytes. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9666-70.