The Rise of Fetal and Neonatal Physiology Basic Science to Clinical
During the mid- to late-twentieth century, study of the physiology of the developing fetus and newborn infant evolved rapidly to become a major discipline in the biomedical sciences. Initially of interest from a standpoint of function of the placenta and
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REVIEW
SUBJECT COLLECTION: MECHANOTRANSDUCTION
Forcing a growth factor response – tissue-stiffness modulation of integrin signaling and crosstalk with growth factor receptors Farhana A. Sarker1,2,*, Victoria G. Prior1,2, *, Samuel Bax1 and Geraldine M. O’Neill1,2,3,‡
ABSTRACT Research throughout the 90s established that integrin crosstalk with growth factor receptors stimulates robust growth factor signaling. These insights were derived chiefly from comparing adherent versus suspension cell cultures. Considering the new understanding that mechanosensory inputs tune adhesion signaling, it is now timely to revisit this crosstalk in different mechanical environments. Here, we present a brief historical perspective on integrin signaling against the backdrop of the mechanically diverse extracellular microenvironment, then review the evidence supporting the mechanical regulation of integrin crosstalk with growth factor signaling. We discuss early studies revealing distinct signaling consequences for integrin occupancy (binding to matrix) and aggregation (binding to immobile ligand). We consider how the mechanical environments encountered in vivo intersect with this diverse signaling, focusing on receptor endocytosis. We discuss the implications of mechanically tuned integrin signaling for growth factor signaling, using the epidermal growth factor receptor (EGFR) as an illustrative example. We discuss how the use of rigid tissue culture plastic for cancer drug screening may select agents that lack efficacy in the soft in vivo tissue environment. Tuning of integrin signaling via external mechanical forces in vivo and subsequent effects on growth factor signaling thus has implications for normal cellular physiology and anti-cancer therapies. KEY WORDS: EGFR, Cancer, Cell adhesion, Integrin, Mechanosensing, Mechanotransduction
quantified. Moreover, invasive cancer cells transmigrate tissues that may be softer than the primary tumor. Considerably less is known about the effect of the entire range of tissue forces exerted on cells in vivo, yet this is likely to have important consequences for cell function. This Review first provides a brief historical perspective on integrin signaling. Next, the evidence supporting mechanical regulation of integrin crosstalk with growth factor signaling is reviewed. Finally, potential mechanisms of mechanical modulation of crosstalk are considered, with the epidermal growth factor receptor (EGFR) as an illustrative example. This Review departs from the many excellent reviews emphasizing the role of a stiff tissue environment by instead exploring how the range of tissue stiffnesses encountered by cells in the body may tune adhesion signaling and modulate the crosstalk between integrins and growth factors, with the attendant consequences for anti-cancer therapies. Tuning in
Far from being a simple mechanism whereby ligand-binding activates downstream signaling, integrin signaling constitutes a hierarchical recruitment of signaling molecules that is modulated by the states of ligand occupanc
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