Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The migrating cell is highly polarized with complex regulatory pathways that spatially and temporally integrate its component processes. This review describes the mechanisms underlying the major steps of migration and the signaling pathways that regulate them, and outlines recent advances investigating the nature of polarity in migrating cells and the pathways that establish it.

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Cell migration: integrating signals from front to back.

The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.

/pdf/cell-mechanics-and-the-cytoskeleton-4jmvbqe21g.pdf

Cell mechanics and the cytoskeleton

The microvascular endothelial cell monolayer localized at the critical interface between the blood and vessel wall has the vital functions of regulating tissue fluid balance and supplying the essential nutrients needed for the survival of the organism. The endothelial cell is an exquisite "sensor" that responds to diverse signals generated in the blood, subendothelium, and interacting cells. The endothelial cell is able to dynamically regulate its paracellular and transcellular pathways for transport of plasma proteins, solutes, and liquid. The semipermeable characteristic of the endothelium (which distinguishes it from the epithelium) is crucial for establishing the transendothelial protein gradient (the colloid osmotic gradient) required for tissue fluid homeostasis. Interendothelial junctions comprise a complex array of proteins in series with the extracellular matrix constituents and serve to limit the transport of albumin and other plasma proteins by the paracellular pathway. This pathway is highly regulated by the activation of specific extrinsic and intrinsic signaling pathways. Recent evidence has also highlighted the importance of the heretofore enigmatic transcellular pathway in mediating albumin transport via transcytosis. Caveolae, the vesicular carriers filled with receptor-bound and unbound free solutes, have been shown to shuttle between the vascular and extravascular spaces depositing their contents outside the cell. This review summarizes and analyzes the recent data from genetic, physiological, cellular, and morphological studies that have addressed the signaling mechanisms involved in the regulation of both the paracellular and transcellular transport pathways.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2005

Signaling Mechanisms Regulating Endothelial Permeability

The actin cytoskeleton is a complex structure that performs a wide range of cellular functions. In 2001, significant advances were made to our understanding of the structure and function of actin m...

Actin Binding Proteins: Regulation of Cytoskeletal Microfilaments

Actin is the most abundant protein in most eukaryotic cells. It is highly conserved and participates in more protein-protein interactions than any known protein. These properties, along with its ability to transition between monomeric (G-actin) and filamentous (F-actin) states under the control of nucleotide hydrolysis, ions, and a large number of actin-binding proteins, make actin a critical player in many cellular functions, ranging from cell motility and the maintenance of cell shape and polarity to the regulation of transcription. Moreover, the interaction of filamentous actin with myosin forms the basis of muscle contraction. Owing to its central role in the cell, the actin cytoskeleton is also disrupted or taken over by numerous pathogens. Here we review structures of G-actin and F-actin and discuss some of the interactions that control the polymerization and disassembly of actin.

Actin structure and function.

The multiple causes and multiple consequences of mammalian heart failure make it an attractive proposition for analysis using gene array technology, especially where the failure is idiopathic in nature. However, gene arrays also hold potential artefacts, particularly when gene expression levels are low, and where changes in expression levels are modest. Also, at present, the number of genes available on arrays is not large enough to prevent potential sampling deficiencies. Thus, it may not be wise to place too much reliance on quantitative interpretations of gene array data. Also, recently doubts were raised about the qualitative reliability of array genes. Electrophoretic methods are slow, cumbersome and complex but they can provide confirmation that the trends and numbers arising from the new gene arrays are reliable. In this overview, we compare gene array data with data from protein activity assays such as zymograms, Western blots, two-dimensional electrophoresis, and immunohistochemistry. Similar or complementary data from the same heart tissues analyzed by either microarrays or macroarrays can be reassuring to those interested in reliable molecular analyses of normal and failing hearts. Similar principles will apply to other tissues and cells.

Heart failure and apoptosis: electrophoretic methods support data from micro- and macro-arrays. A critical review of genomics and proteomics.

We examine the reliability and accuracy of gene array technology in analyzing differences in gene expression between human non-diseased left atrium and left ventricle We have used cDNA gene arrays and validated those data by carefully designed quantitative real-time polymerase chain reaction (PCR) We have identified pitfalls using cDNA gene array technology based on comparisons with other gene array studies and with changes reported for the levels of expression of the genes corresponding to these cDNAs The high error rate reported here underscores the cautionary comments reported by others in this field

Comparison of gene expression between left atria and left ventricles from non-diseased humans.

Heart failure (HF) is one of the leading causes of combined morbidity and mortality among developed nations. It is the final clinical presentation of a variety of cardiovascular diseases and disorders, such as coronary artery disease, hypertension, valvular heart disease, myocarditis, diabetes, alcohol abuse, and familial cardiomyopathies (Narula et al. 1996). This pathophysiological state is characterized by progressive deterioration of ventricular function, usually in the left ventricle (LV). Pathologic stressors and increased demands for cardiac work result in compensatory mechanisms, such as hypertrophy of cardiomyocytes, increased sympathetic activity, and activation of the rennin–angiotensin–aldosterone system (Curtiss et al. 1978; Levine et al. 1982; Pfeffer et al. 1988; Anversa, Olivetti and Capasso 1991). These short-term adaptive mechanisms eventually become maladaptive and lead to HF. Understanding the mechanisms underlying HF has been difficult since it arises from the interaction between environmental factors and genetic susceptibility, and cannot be explained by a single gene or pathway (Seidman and Seidman 2001). Considerable research has been undertaken to explain why short-term compensatory mechanisms often become maladaptive in the long term. This chapter will focus on mutations in actin within the heart (both sarcomeric and cytoskeletal) and alterations in the actin binding proteins (ABPs) that interact with actin. (For a detailed discussion see the chapter by Sparrow and Laing.)

Actin and Its Binding Proteins in Heart Failure

Recent developments in microarray technology in determining the protein and gene content of cellular extracts will allow, on a much larger scale, the characterization of genes and proteins that change due to heart failure.


Keywords:

microarrays;
cardiomyopathy;
heart failure;
apoptosis;
genomics

Masako Tsubakihara

Papers

Actin Binding Proteins: Regulation of Cytoskeletal Microfilaments

Heart failure and apoptosis: electrophoretic methods support data from micro- and macro-arrays. A critical review of genomics and proteomics.

Comparison of gene expression between left atria and left ventricles from non-diseased humans.

Actin and Its Binding Proteins in Heart Failure

Proteomics and Genomics Technology: Comparison in Heart Failure and Apoptosis