Positional Control of Cell Fate Through Joint Integrin/Receptor Protein Kinase Signaling

Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Annual Review of Cell and Developmental Biology (Impact Factor: 16.66). 11/2003; 19(1):173-206. DOI: 10.1146/annurev.cellbio.19.031103.133334
Source: PubMed


Cells adhere to the extracellular matrix throughout most of their lifetime. This close, intimate contact with the matrix exerts an extraordinary control on the behavior of cells, determining whether they move or stay put, proliferate or remain quiescent, and even live or die. Attachment to the matrix not only enables cells to respond to soluble growth factors and cytokines but also determines the nature of the response. The integrins are a large family of receptors that attach cells to the matrix, organize their cytoskeleton, and cooperate with receptor protein tyrosine kinases to regulate cell fate. Research on integrin signaling is beginning to explain the complex and specific effects that the extracellular matrix exerts on cells.

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    • "In addition, Fn1 binds a number of growth factors, including VEGF, HGF, and many Fgfs (Giancotti and Tarone, 2003; Hynes, 2009; Martino and Hubbell, 2010; Miyamoto et al., 1996; Wijelath et al., 2002). Many growth factors require integrin-mediated cell adhesion to Fn1 for signaling (Giancotti and Tarone, 2003; Miyamoto et al., 1996). Taken together, these studies suggest that the enrichment of Fn1 in distinct embryonic regions may be important to modulate cellular responses to growth factors and to regulate specific morphogenetic processes. "
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    ABSTRACT: Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in the pharyngeal region may be essential for cardiovascular morphogenesis. To test this hypothesis, we ablated Fn1 using the Isl1(Cre) knock-in strain of mice. Deletion of Fn1 using the Isl1(Cre) strain resulted in defective formation of the 4th pharyngeal arch arteries (PAAs), aberrant development of the cardiac outflow tract (OFT), and ventricular septum defects. To determine the cell types responding to Fn1 signaling during cardiovascular development, we deleted a major Fn1 receptor, integrin α5 using the Isl1(Cre) strain, and observed the same spectrum of abnormalities seen in the Fn1 conditional mutants. Additional conditional mutagenesis studies designed to ablate integrin α5 in distinct cell types within the Isl1(+) tissues and their derivatives, suggested that the expression of integrin α5 in the pharyngeal arch mesoderm, endothelium, surface ectoderm and the neural crest were not required for PAA formation. Our studies suggest that an (as yet unknown) integrin α5-dependent signal extrinsic to the pharyngeal endothelium mediates the formation of the 4th PAAs.
    Full-text · Article · Oct 2015 · Developmental Biology
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    • "Besides controlling GF bioavailability, the ECM also modulates GF signaling through the interplay between GFs, ECM proteins, cell-adhesion receptors, and GF receptors (Giancotti and Tarone, 2003; Hynes, 2009; Kim et al., 2011). For example, the binding of VEGF 165 to fibronectin forms molecular complexes that induce the formation of clusters between VEGF receptor and integrins (Wijelath et al., 2006; Martino et al., 2011, 2013). "
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    ABSTRACT: Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis onVEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.
    Full-text · Article · Apr 2015 · Frontiers in Bioengineering and Biotechnology
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    • "Adhesion by integrin-mediated junctions allows tissues to withstand mechanical load and is essential for tissue integrity. Integrinbased signalling regulates cell migration, division, and differentiation (Bokel and Brown, 2002; Giancotti and Tarone, 2003; Meighan and Schwarzbauer, 2008). Thus, integrins are the major family of cell surface receptors that mediate cell attachment to the extracellular matrix and can mediate cell– cell interactions (Hynes, 1992; Hynes 1999; Li and Sakaguchi, 2002). "
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    ABSTRACT: How the neural retina is held in its place in the human physiological living body) Bratislava 2014 Original self-publishing first edition of the monograph, entitled " Gergely's retinal linkage (How the neural retina is held in its place in the human physiological living body) " by Gergely K (contact:; affiliation: Faculty of Medicine in Bratislava, Comenius University in Bratislava, Slovak Republic; This work may not be translated or copied in whole or in part without the written permission of the publisher Květoslava Gergelyova, MD; Prague, Czech Republic (contact:, except for brief excerpts in connection with scientific articles or scholarly analysis [regular citation: Gergely K. Gergely's retinal linkage (How the neural retina is held in its place in the human physiological living body). Publisher Gergelyova, 2014]. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.
    Full-text · Book · Dec 2014
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