COMMENTARY
Nonmuscle Motility/Cytoskeleton

Kathleen G. Morgan, Associate Editor

American Journal of Physiology-Cell Physiology, Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472, (E-mail: morgan{at}bbri.org), June 2001, Volume 280 (49)


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THE FIELD OF "MUSCLE PHYSIOLOGY" has traditionally included the study of mechanisms of contraction of striated and smooth muscles under normal and pathophysiological conditions. This special call for papers was initiated to recognize the fact that the field has now evolved and expanded to include complex considerations of the function and assembly of the cytoskeleton as well as mechanisms of "nonmuscle motility." Nonmuscle motility may at first seem a bit of an oxymoron, but the term reflects the fact that actin and myosin regulate not just contraction but also cell crawling, chemotaxis, cell shape, cytokinesis, and phagocytosis, to name a few.

It has been known for some time that smooth muscle cells can crawl as well as contract. Some investigators have suggested that extracellular signal-regulated kinase/mitogen-activated protein kinases (ERK/MAPK) and the actin binding protein caldesmon might regulate smooth muscle contractility (1, 4, 5), although this remains highly controversial (3, 9). Now, Yamboliev and Gerthoffer (Ref. 12, see p. C1680 in this issue) provide evidence that ERK/MAPK, possibly through phosphorylation of caldesmon, can modulate smooth muscle cell migration once it is initiated by appropriate signaling pathways.

The division between muscle physiology and cell biology has become less clear as the demonstration of the increasingly complex roles of actin in muscle and nonmuscle cells has progressed. Clearly, actin and actin binding proteins regulate myosin activity. However, actin, together with the microtubules and intermediate filaments, also forms an internal skeleton to physically support the cell. Where the story has become especially complex (and interesting) is the realization that signal transduction mechanisms are regulated by cytoskeletal components.

Rosado et al. (Ref. 10, see p. C1636 in this issue) suggests that reorganization of the actin cytoskeleton, modulated by tumor necrosis factor-alpha , regulates store-mediated Ca2+ entry in a human hepatocellular carcinoma cell line. Similarly, Hamm-Alvarez et al. (Ref. 7, see p. C1657 in this issue) present evidence that cytoplasmic non-receptor tyrosine kinases, cytoskeletal components, and the regulation of cell-to-cell signaling are interrelated.

It has long been assumed that the actin cytoskeleton is a rather static structure in differentiated muscle, but Conley (Ref. 2, see p. C1645 in this issue), reporting on leiomodin and tropomodulin in smooth muscle, makes the highly speculative but intriguing suggestion that the smooth muscle cytoskeleton is in a state of dynamic flux leading to actin filament remodeling during muscle contraction. Although this remains a controversial topic, a body of evidence is growing to support this concept (reviewed in Ref. 6), and further investigation of actin capping proteins in differentiated muscle may be warranted.

Cultured fibroblasts offer a model system for the study of cytoskeletal function. Katoh et al. (Ref. 8, see p. C1669 in this issue) provide evidence that there are two functionally different types of stress fibers in these cells: central and peripheral stress fibers. These authors suggest that the peripheral fibers are regulated, like classic smooth muscle contractile filaments, by myosin light chain kinase but that the central fibers are regulated primarily by Rho kinase. These studies have implications not only for fibroblast cell biology but also for smooth muscle physiologists who have suspected that both kinases may play a role in the regulation of contraction (11).

The determination of the precise role of cytoskeletal components in the regulation of the physiology of muscle and nonmuscle cells poses considerable challenges. Physiologists are often interested in differentiated cells that are difficult to perturb with molecular precision. Furthermore, these perturbations often demonstrate tantalizing correlations, but true cause-and-effect relationships often prove elusive. Despite these difficulties, the field is clearly growing and merits the attention of physiologists not just in the muscle field but also those studying nonmuscle cells, i.e., essentially all tissues in the body.


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1.   Adam, LP, and Hathaway DR. Identification of mitogen-activated protein kinase phosphorylation sequences in mammalian h-caldesmon. FEBS Lett 322: 56-60, 1993[ISI][Medline].

2.   Conley, CA. Leiomodin and tropomodulin in smooth muscle. Am J Physiol Cell Physiol 280: C1645-C1656, 2001[Abstract/Free Full Text].

3.   D'Angelo, G, Graceffa P, Wang C-LA, Wrangle J, and Adam LP. Mammal-specific, ERK-dependent, caldesmon phosphorylation in smooth muscle. J Biol Chem 274: 30115-30121, 1999[Abstract/Free Full Text].

4.   Dessy, C, Kim I, Sougnez CL, Laporte R, and Morgan KG. A role for MAP kinase in differentiated smooth muscle contraction evoked by alpha -adrenoceptor stimulation. Am J Physiol Cell Physiol 275: C1081-C1086, 1998[Abstract/Free Full Text].

5.   Gerthoffer, WT, Yamboliev IA, Shearer M, Pohl J, Haynes R, Dang S, Sato K, and Sellers JR. Activation of MAP kinases and phosphorylation of caldesmon in canine colonic smooth muscle. J Physiol (Lond) 495: 597-609, 1996[Abstract].

6.   Gunst, SJ, and Tang DD. The contractile apparatus and mechanical properties of airway smooth muscle. Eur Respir J 15: 600-616, 2000[Abstract/Free Full Text].

7.   Hamm-Alvarez, SF, Chang A, Wang Y, Jerdeva G, Lin HH, Kim K-J, and Ann DK. Etk/Bmx activation modulates barrier function in epithelial cells. Am J Physiol Cell Physiol 280: C1657-C1668, 2001[Abstract/Free Full Text].

8.   Katoh, K, Kano Y, Amano M, Kaibuchi K, and Fujiwara K. Stress fiber organization regulated by MLCK and Rho-kinase in cultured human fibroblasts. Am J Physiol Cell Physiol 280: C1669-C1679, 2001[Abstract/Free Full Text].

9.   Nixon, GF, Iizuka K, Haystead CMM, Haystead TAJ, Somlyo AP, and Somlyo AV. Phosphorylation of caldesmon by mitogen-activated protein kinase with no effect on Ca2+ sensitivity in rabbit smooth muscle. J Physiol (Lond) 487: 283-289, 1995[Abstract].

10.   Rosado, JA, Rosenzweig I, Harding S, and Sage SO. Tumor necrosis factor-alpha inhibits store-mediated Ca2+ entry in the human hepatocellular carcinoma cell line HepG2. Am J Physiol Cell Physiol 280: C1636-C1644, 2001[Abstract/Free Full Text].

11.   Somlyo, AP, and Somlyo AV. Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol (Lond) 522: 177-185, 2000[Abstract/Free Full Text].

12.   Yamboliev, IA, and Gerthoffer WT. Modulatory role of ERK MAPK-caldesmon pathway in PDGF-stimulated migration of cultured pulmonary artery SMCs. Am J Physiol Cell Physiol 280: C1680-C1688, 2001[Abstract/Free Full Text].


Am J Physiol Cell Physiol 280(6):C1634-C1635
0363-6143/01 $5.00 Copyright © 2001 the American Physiological Society