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Tian R.,Lunenfeld Tanenbaum Research Institute
Proteomics | Year: 2014

Cells live in a close social context by having mutual communication with their local microenvironment. This complex intercellular communication activates dynamic signaling pathways and regulates specific cell fate. MS-based proteomics has been approved to be inevitable for characterizing dynamic protein expression and PTMs on a global scale. However, because of technical difficulties for targeting membrane receptors and secreted proteins, especially in a physiologically relevant manner, systematic characterization of intercellular signaling by MS-based proteomics has largely lagged behind. Here, I will review the latest proteomics technology development and its application to characterizing different modes of intercellular communication including indirect and direct cell-cell communication, and protein translocalization. I will discuss how MS-based proteomics has been applied for systems-level profiling intercellular signaling in defined biological contexts including tumor microenvironment, bacteria/virus-host cell interaction, immune cell interaction, and stem cell niche. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Mennella V.,University of California at San Francisco | Agard D.A.,University of California at San Francisco | Huang B.,University of California at San Francisco | Pelletier L.,Lunenfeld Tanenbaum Research Institute | Pelletier L.,University of Toronto
Trends in Cell Biology | Year: 2014

The centrosome influences the shape, orientation and activity of the microtubule cytoskeleton. The pericentriolar material (PCM), determines this functionality by providing a dynamic platform for nucleating microtubules and acts as a nexus for molecular signaling. Although great strides have been made in understanding PCM activity, its diffraction-limited size and amorphous appearance on electron microscopy (EM) have limited analysis of its high-order organization. Here, we outline current knowledge of PCM architecture and assembly, emphasizing recent super-resolution imaging studies that revealed the PCM has a layered structure made of fibers and matrices conserved from flies to humans. Notably, these studies debunk the long-standing view of an amorphous PCM and provide a paradigm to dissect the supramolecular organization of organelles in cells. © 2013 Elsevier Ltd.


Nagy A.,Lunenfeld Tanenbaum Research Institute | Nagy A.,University of Toronto
Current Opinion in Genetics and Development | Year: 2013

The groundbreaking discovery of the induced pluripotent stem cells in 2006 [. 1] brought a major paradigm shift in our understanding of the plasticity of differentiated cells. An unprecedented effort has been invested to elucidate the underpinning molecular mechanisms of the dramatic changes in cell properties, using the powerful secondary reprogramming systems (2°RS). This review outlines the key components of the 2°RS, its recent development and applications that have led to a deeper understanding of the 'magic' of induced cell fate changes. © 2013 Elsevier Ltd.


Rosario C.O.,Lunenfeld Tanenbaum Research Institute
Oncogene | Year: 2014

Polo family kinase 4 (Plk4) is required for mitotic progression, and is haploinsufficient for tumor suppression and timely hepatocyte polarization in regenerating liver. At the same time, recent evidence suggests that Plk4 expression may have a role in clinical cancer progression, although the mechanisms are not clear. Here we identify a gene expression pattern predictive of reduced motility in Plk4+/- murine embryonic fibroblasts (MEFs) and validate this prediction with functional assays of cell spreading, migration and invasion. Increased Plk4 expression enhances cell spreading in Plk4+/- MEFs and migration in human embryonic kidney 293T cells, and increases invasion by DLD-1 colon cancer cells. Plk4 depletion impairs invasion of wild-type MEFs and suppresses invasion by MDA-MB231 breast cancer cells. Cytoskeletal reorganization and development of polarity are impaired in Plk4-deficient cells that have been stimulated to migrate. Endogenous Plk4 phosphorylated at the autophosphorylation site S305 localizes to the protrusions of motile cells, coincident with the RhoA GEF Ect2, GTP-bound RhoA and the RhoA effector mDia. Taken together, our findings reveal an unexpected activity of Plk4 that promotes cell migration and may underlie an association between increased Plk4 expression, cancer progression and death from metastasis in solid tumor patients.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.275.


Lal H.,Vanderbilt University | Ahmad F.,Vanderbilt University | Woodgett J.,Lunenfeld Tanenbaum Research Institute | Force T.,Vanderbilt University
Circulation Research | Year: 2015

Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer disease, aging, inflammation, and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review, we will focus on its expanding role in the heart, concentrating primarily on recent studies that have used cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis, and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3α specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction after myocardial infarction by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3β as a regulator of myocardial fibrosis will also be discussed. We will review our recent findings that specific deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3β is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature. © 2014 American Heart Association, Inc.

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