Growing evidence indicates that the slender actin-based extensions known as filopodia play central roles in the cell biology underlying inflammation and angiogenesis. The initial contacts between leukocytes and endothelial cells during leukocyte rolling occur at the tips of filopodia-like structures and endothelial """"""""pathfinder"""""""" cells appear to be guided by filopodia during angiogenesis. Despite these critical roles of filopodia in leukocytes and endothelial cells, the molecular mechanisms underlying filopodial extension, adhesion, and signaling are largely unknown. Our discovery that myosin-X (Myo10) is a core component of a putative filopodial tip complex, is involved in filopodia formation, and undergoes a novel form of motility in filopodia, gives us a powerful tool to investigate these questions. We therefore propose to: I. Determine the functional consequences of MyolO's interaction with integrins. Since Myo10 is an unconventional myosin whose tail includes a PERM domain that can binds to the cytoplasmic domains of pintegrins, we will test whether binding to this motor protein activates integrins. We will also test if Myo10 binds to the leukocyte specific beta2-integrins and if Myo10 is required for complement-mediated phagocytosis. II. Analyze the functions of Myo10 in leukocytes and endothelial cells in processes such as filopodial extension, chemotaxis, and transendothelial migration using siRNA and a dominant negative construct. Although Myo10 is the MyTH-FERM myosin expressed in most vertebrate cells and a related myosin in lower organisms is required for filopodia formation, adhesion, and phagocytosis, almost nothing is known about the functions of this family of myosins in leukocytes and endothelial cells. III. Define the basic biochemical properties and components of the filopodial tip complex. Like the focal adhesion, the filopodial tip complex appears to function as a specialized site of cell adhesion, signaling, and actin polymerization, but currently very little is known about the molecular components and properties of the filopodial tip complex. This work is of great relevance to public health because it will investigate the fundamental cell biological mechanisms of inflammation and cell signaling that underlie cardiovascular disease and other serious human health problems.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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University of North Carolina Chapel Hill
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Shaaban, Khaled A; Singh, Shanteri; Elshahawi, Sherif I et al. (2014) The native production of the sesquiterpene isopterocarpolone by Streptomyces sp. RM-14-6. Nat Prod Res 28:337-9
Lessey-Morillon, Elizabeth C; Osborne, Lukas D; Monaghan-Benson, Elizabeth et al. (2014) The RhoA guanine nucleotide exchange factor, LARG, mediates ICAM-1-dependent mechanotransduction in endothelial cells to stimulate transendothelial migration. J Immunol 192:3390-8
Totani, Licia; Piccoli, Antonio; Dell'Elba, Giuseppe et al. (2014) Phosphodiesterase type 4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury. Arterioscler Thromb Vasc Biol 34:1689-96
Wittchen, Erika S; Nishimura, Eiichi; McCloskey, Manabu et al. (2013) Rap1 GTPase activation and barrier enhancement in rpe inhibits choroidal neovascularization in vivo. PLoS One 8:e73070
Samson, Thomas; van Buul, Jaap D; Kroon, Jeffrey et al. (2013) The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis. PLoS One 8:e55202
Gross, A Kendall; Dunn, Steven P; Feola, David J et al. (2013) Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness. J Thromb Thrombolysis 35:147-54
Monaghan-Benson, E; Burridge, K (2013) Mutant B-RAF regulates a Rac-dependent cadherin switch in melanoma. Oncogene 32:4836-44
Lessey, Elizabeth C; Guilluy, Christophe; Burridge, Keith (2012) From mechanical force to RhoA activation. Biochemistry 51:7420-32
Yang, Fanmuyi; Dong, Anping; Mueller, Paul et al. (2012) Coronary artery remodeling in a model of left ventricular pressure overload is influenced by platelets and inflammatory cells. PLoS One 7:e40196
Liu, Katy C; Jacobs, Damon T; Dunn, Brian D et al. (2012) Myosin-X functions in polarized epithelial cells. Mol Biol Cell 23:1675-87

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