No abstract

Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multiprotein structures that link the ECM to the cytoplasmic actin cytoskeleton. These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization. In motile cells, sites of adhesion within ®lopodia and lamellipodia are relatively small and transient and are referred to as`focal complexes,' whereas adhesions underlying the body of the cell and localized to the ends of actin stress ®bers are referred to as`focal adhesions'. Signal transduction through focal complexes and focal adhesions has been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival and cell locomotion. The formation and remodeling of focal contacts is a dynamic process under the regulation of protein tyrosine kinases and small GTPases of the Rho family. In this review, we consider the role of the focal complex associated protein tyrosine kinase, Focal Adhesion Kinase (FAK), in the regulation of cell movement with the emphasis on how FAK regulates the¯ow of signals from the ECM to the actin cytoskeleton. Oncogene (2000) 19, 5606 ± 5613.

The integrin family of cell surface receptors mediates cell adhesion to components of the extracellular matrix (ECM). Integrin engagement with the ECM initiates signaling cascades that regulate the organization of the actin-cytoskeleton and changes in gene expression. The Rho subfamily of Ras-related low-molecular-weight GTP-binding proteins and several protein tyrosine kinases have been implicated in mediating various aspects of integrin-dependent alterations in cell homeostasis. Focal adhesion kinase (FAK or pp125 FAK ) is one of the tyrosine kinases predicted to be a critical component of integrin signaling. To elucidate the mechanisms by which FAK participates in integrin-mediated signaling, we have used expression cloning to identify cDNAs that encode potential FAK-binding proteins. We report here the identification of a cDNA that encodes a new member of the GTPase-activating protein (GAP) family of GTPase regulators. This GAP, termed Graf (for GTPase regulator associated with FAK), binds to the C-terminal domain of FAK in an SH3 domain-dependent manner and preferentially stimulates the GTPase activity of the GTP-binding proteins RhoA and Cdc42. Subcellular localization studies using Graf-transfected chicken embryo cells indicates that Graf colocalizes with actin stress fibers, cortical actin structures, and focal adhesions. Graf mRNA is expressed in a variety of avian tissues and is particularly abundant in embryonic brain and liver. Graf represents the first example of a regulator of the Rho family of small GTP-binding proteins that exhibits binding to a protein tyrosine kinase. We suggest that Graf may function to mediate cross talk between the tyrosine kinases such as FAK and the Rho family GTPases that control steps in integrin-initiated signaling events.Integrin-mediated cell adhesion to the extracellular matrix (ECM) has both structural and biochemical ramifications for cell homeostasis (31). Integrins bind components of the ECM via large extracellular domains. These sites of integrin-ECM interaction trigger the formation of protein complexes on the cytoplasmic face of the plasma membrane termed focal adhesions. Focal adhesions contain several proteins with the capacity to simultaneously bind the short cytoplasmic tails of integrins and actin filaments. Thus, focal adhesions serve to anchor the actin cytoskeleton to the plasma membrane and directly link the extracellular and intracellular environments (10). Besides playing a structural role, the binding of integrins to ECM results in the initiation of intracellular signaling cascades (17,49). Activation of these cascades has been proposed to regulate gene expression (22, 66), cell survival (8, 54), cell migration and adhesion, and differentiation (31). Recent studies have generated an extensive list of potential mediators of integrin signaling, including the cytoplasmic protein kinases focal adhesion kinase (pp125 FAK or FAK) (55), pp60 src (18, 35, 55), pp59 fyn (18), C-terminal Src kinase (Csk) (4), and protein kinase C isoforms ␣ and ␦ (2, 32); th...

High-intensity interval trainingHigh-intensity interval training is a form of exercise training characterized by bursts of high-intensity activity followed by less intense recovery periods.

Skeletal muscle cells are highly abundant and metabolically active and are known to ‘communicate’ their energy demands to other organs through active secretion. Muscle-derived secretory proteins include a variety of cytokines and peptides collectively referred to as “myokines” that exert auto-, para- or endocrine effects. Analyses of the skeletal muscle secretome revealed that numerous myokines are secreted in response to contraction or strength training, and that these factors not only regulate energy demand but also contribute to the broad beneficial effects of exercise on cardiovascular, metabolic, and mental health. Herein we review recent studies on the myokines that regulate muscle function and those that mediate cross talk between skeletal muscle and other organs including adipose tissue, liver, pancreas, the cardiovascular system, brain, bones, and skin.