The Matrix Reorganized: Extracellular Matrix Remodeling and Integrin Signaling Melinda Larsen1, Vira V Artym1,2, J Angelo Green1 and Kenneth M Yamada1
Total Page：16
File Type：pdf, Size：1020Kb
The matrix reorganized: extracellular matrix remodeling and integrin signaling Melinda Larsen1, Vira V Artym1,2, J Angelo Green1 and Kenneth M Yamada1 Via integrins, cells can sense dimensionality and other physical (2D) surfaces and complex, malleable three-dimensional and biochemical properties of the extracellular matrix (ECM). (3D) environments can therefore be sensed by integrins Cells respond differently to two-dimensional substrates and that respond to these surfaces with altered signaling three-dimensional environments, activating distinct signaling (reviewed in [3–7]). pathways for each. Direct integrin signaling and indirect integrin modulation of growth factor and other intracellular signaling In this review, we discuss recent findings regarding ECM pathways regulate ECM remodeling and control subsequent remodeling, with emphasis on collagen, fibronectin and cell behavior and tissue organization. ECM remodeling is associated integrin signaling. We examine how ECM critical for many developmental processes, and remodeled physical properties and higher-order organization influ- ECM contributes to tumorigenesis. These recent advances in ence cell behavior and integrin signaling pathways. ECM the field provide new insights and raise new questions about remodeling is required in vivo for proper development, the mechanisms of ECM synthesis and proteolytic degradation, but ECM alterations can also create an environment as well as the roles of integrins and tension in ECM remodeling. conducive to tumorigenesis. In this review, we will con- Addresses sider some examples of these processes. We apologize for 1 Craniofacial Developmental Biology and Regeneration Branch, the omissions imposed by the need for brevity. National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, MSC 4370, Bethesda, MD 20892-4370, USA Fibroblast-mediated collagen matrix 2 Department of Oncology, Lombardi Comprehensive Cancer Center, remodeling in vitro Georgetown University Medical School, Washington, DC 20057-1469, Increasing numbers of studies show that the morphology, USA cytoskeletal structure and signaling of cells grown on 2D surfaces differ from those of cells grown within 3D Corresponding author: Yamada, Kenneth M ([email protected]) environments, where collagen fibers contact both ventral (lower) and dorsal (upper) surfaces of the cells. In fact, Current Opinion in Cell Biology 2006, 18:463–471 upon engagement of receptors on their dorsal surface, well-spread fibroblasts in 2D culture quickly convert to a This review comes from a themed issue on Cell-to-cell contact and extracellular matrix bipolar or stellate morphology characteristic of fibroblasts Edited by Martin Schwartz and Alpha Yap in 3D environments [8 ]. A recent study [9] of cell interactions with collagen reveals that a2b1 integrin- Available online 17th August 2006 mediated transport of collagen fibers and subsequent 0955-0674/$ – see front matter contraction of in vitro 3D collagen matrices requires # 2006 Elsevier Ltd. All rights reserved. non-muscle myosin II-B. Although this myosin is impor- tant for fibroblast cell motility in 3D collagen matrices, it DOI 10.1016/j.ceb.2006.08.009 is not required for migration on 2D surfaces. Another difference is that myosin II-B only localizes to cellular extensions when cells are plated within 3D matrices Introduction rather than on 2D surfaces [9]. Extracellular matrix (ECM) remodeling is involved in development, fibrosis, tissue repair and tumor-associated Specific serum components can facilitate integrin-depen- desmoplasia (stromatogenesis). The ECM can be remo- dent 3D collagen gel contraction through different sig- deled by many processes, including synthesis, contraction naling pathways. PDGF-stimulated contraction of and proteolytic degradation. Integrins are the primary floating collagen matrices utilizes phosphatidylinositol ECM receptors mediating ECM remodeling (reviewed 3-kinase (PI3K) and myosin II, whereas LPA-stimulated in [1,2]). In response to changes in the ECM, integrin contraction depends on signaling by the monomeric G- signaling also regulates many other interrelated cellular protein GaI, but does not require myosin II [10,11 ]. processes: proliferation, survival, cell migration and inva- Using siRNA knockdown and inhibitors, it was demon- sion (Figure 1). Integrins function as mechanotransducers strated that signaling through PDGF and LPA converge and can transform mechanical forces created by the ECM on p21-activated kinase-1 (PAK1) to regulate collagen or the cytoskeleton into chemical signals. Differences matrix contraction through cofilin-1 [11]. PAK1 there- between simple, rigid and non-pliable two-dimensional fore links these two distinct matrix remodeling pathways. www.sciencedirect.com Current Opinion in Cell Biology 2006, 18:463–471 464 Cell-to-cell contact and ECM Figure 1 Generalized schematic diagram of integrin signaling, focusing on pathways specifically covered in this review. Integrins signal through recruitment of FAK, recruitment and activation of SFKs, and activation of PI3K. Src phosphorylates p130CAS and recruits Crk to activate Rac. Rac is also activated by FAK via stimulation from PIX/GIT/paxillin complexes. FAK activates ERK signaling that, together with Rac downstream signaling, exerts a regulatory effect on cell proliferation and survival. Signaling downstream of PI3K affects activation of Akt and the small GTPases Rac, Cdc42, and Rho to induce changes in the cytoskeleton, cell contractility, cell migration, invasion and gene expression. Crosstalk between integrin and GFR signaling pathways ensures proper integration of integrin- and GFR-mediated signaling required for optimal cell function. LPA, acting through a seven-transmembrane G-protein-coupled receptor, signals through PAK and cofilin, and cooperates with the ROCK/MLCP/myosin II pathway to promote collagen matrix contraction. Abbreviations: guanine nucleotide-exchange factors, GEFs; growth factor, GF; LIM kinase, LIMK; mammalian diaphanous, mDIA; myosin light chain phosphatase, MLCP; phosphatidylinositol-3,4,5-trisphosphate, PIP3; protein kinase C, PKC; Src-family kinases, SFKs; Wiskott-Aldrich syndrome protein, WASP. ROCK was specifically implicated in PDGF-induced and is well known that conformation directly affects integrin mDia1 in LPA-induced ECM contraction. These findings activation state and ligand-binding activity; in 2D sub- suggest that Rho effectors act parallel to and/or coopera- strates, exogenous activating antibodies or manganese can tively with PAK1 to regulate contraction of floating col- activate integrins and induce matrix formation [1]. lagen matrices. Recent studies implicate the urokinase-type plasminogen Fibronectin matrix remodeling by fibroblasts activator receptor (uPAR) in regulating integrin a5b1 activ- in vitro ity. Addition of a uPAR ligand, the P-25 peptide, stimu- The major receptor for fibronectin, a5b1 integrin, can be lated fibronectin fibril assembly [14] by activating integrin found in different adhesion structures, such as focal a5b1 through the EGF receptor and Src [15]. Interestingly, complexes, focal adhesions, fibrillar adhesions and 3D- fibronectin fibril assembly by cells expressing activation- matrix adhesions [3]. Fibronectin fibrillogenesis is dependent integrins can be stimulated specifically by a 3D mediated by actin-dependent, directed translocation of fibronectin matrix without exogenous activators [16]. a5b1 out of focal adhesions into fibrillar adhesions [12], These data support the idea that a 3D matrix can activate and a recent study indicates that this translocation integrins to induce fibronectin matrix assembly (Figure 2), depends upon a specific integrin conformation [13]. It although the mechanism remains to be elucidated. One Current Opinion in Cell Biology 2006, 18:463–471 www.sciencedirect.com Extracellular matrix remodeling and integrin signaling Larsen, Artym, Green and Yamada 465 Figure 2 located at the basal surface of differentiated epithelial cells. ECM remodeling and integrin signaling are clearly important for branching, especially in the salivary gland, where fibronectin and its major receptor, integrin a5b1, are required (Figure 3a) [21]. Fibronectin accumulation in cleft sites is associated with a decrease in E-cadherin, the prototypic epithelial cadherin that mediates cell–cell adhesion. In this study [21], exogenous cellular fibronec- tin also locally decreased cadherin levels in a human salivary gland cell line, indicating that a function of fibronectin is negative regulation of E-cadherin, although the mechanism of this inhibition is not known. Many classical studies point to the importance of base- ment membrane remodeling during branching morpho- Extracellular factors promote ECM remodeling by stimulating integrin genesis. Recently, cytoskeletal tension was found to be activation. On a 2D substrate in vitro, fibroblast cells are polarized such important for branching: inhibitors of ROCK, myosin that only the ventral surface contacts the substrate. In this state, cells light chain kinase and myosin ATPase inhibited branch- are typically well-spread and only a subset of integrins is activated: bent ing of lung rudiments (Figure 3b) [22]. Interestingly, conformation, inactive integrin; extended conformation, activated ROCK stimulated basement membrane thinning at the integrin. Upon plating within a 3D matrix or following treatment with exogenous stimulators (e.g. Mn2+, activating antibodies or uPAR ligand), lung bud distal tips.