Professor, Department of Biochemistry
Director, Belfer Institute for Advanced Biomedical Studies
Mechanisms of Cell Motility and Metastasis
Cell migration, cytokinesis and the maintenance of cell morphology are fundamental force-requiring processes of eukaryotic cells. Myosin-II is an essential contractile protein and although myosin-II filament dynamics are under strict temporal and spatial control, the mechanisms controlling filament assembly and disassembly in higher eukaryotes are not known. We are specifically addressing how covalent modification (i.e., phosphorylation) and noncovalent interactions with novel regulatory proteins mediate the subcellular localization, organization and assembly of myosin-II during chemotactic motility. These studies will provide new information regarding the molecular signals regulating myosin-II organization during normal cell physiology as well as the pathologies contributing to tumor cell invasion and metastasis.
Phosphorylation of nonmuscle myosin-II on the heavy chain regulates filament assembly and is attributed to several kinases. We showed that heavy chain phosphorylation regulates the chemotactic motility of tumor cells. Moreover, genes coding for proteins that modulate the myosin-II regulatory pathway are up-regulated in invasive tumor cells. Given these findings, we are examining the intermediary signaling pathways in tumor cells that regulate heavy chain phosphorylation and the subsequent effects on motility and invasion. Our interdisciplinary approach combines biochemistry and structural biology to define the physical and chemical features underlying the regulation of myosin-II assembly, and molecular and cellular techniques coupled with fluorescence microscopy to investigate how phosphorylation regulates myosin-II dynamics in vivo.
We are also studying S100A4, a Ca2+-binding protein that directly regulates tumor cell motility and tumor metastasis. We are taking a global approach to dissecting S100A4 function that includes biochemical and structural approaches to identify the mechanisms by which S100A4 regulates the activity of its protein targets and animal studies to evaluate the role of S100A4 in tumor metastasis. In addition, we developed several assays to screen for S100A4 small molecule inhibitors. These efforts will allow for the identifcation and characterization of S100A4 inhibitors that may as leads for anti-metastasis therapeutics.
House RP, Garrett SC and Bresnick AR (2012) Chapter 4: “Moving Aggressively: S100A4 and Tumor Invasion, In: Signaling Pathways and Molecular Mediators in Metastasis”, A. Fatatis ed., Springer, pp 91-113.
Malashkevich V, Dulyaninova NG, Ramagopal UA, Liriano MA, Varney KM, Knight D, Brenowitz M, Weber DJ, Almo SC and Bresnick AR (2010) Phenothiazines inhibit S100A4 function by inducing protein oligomerization. PNAS 107, 8605-10.
Li Z-H, Dulyaninova NG, House RP, Almo SC and Bresnick AR (2010) S100A4 regulates macrophage chemotaxis. Mol Biol Cell 21, 2598-610.
Dulyaninova NG, House RP, Betapudi V and Bresnick AR (2007) Myosin-IIA heavy chain phosphorylation regulates the motility of MDA-MB-231 carcinoma cells. Mol Biol Cell 18, 3144-55.
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