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Laminin Deposition in the Extracellular Matrix: a Complex Picture Emerges

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Laminin Deposition in the Extracellular Matrix: a Complex Picture Emerges Commentary 4409 Laminin deposition in the extracellular matrix: a complex picture emerges Kevin J. Hamill, Kristina Kligys, Susan B. Hopkinson and Jonathan C. R. Jones* Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA *Author for correspondence ([email protected]) Journal of Cell Science 122, 4409-4417 Published by The Company of Biologists 2009 doi:10.1242/jcs.041095 Summary Laminins are structural components of basement membranes. of signaling pathways that are involved in laminin-matrix In addition, they are key extracellular-matrix regulators of cell deposition and on how laminin patterns might play an adhesion, migration, differentiation and proliferation. This important role in specifying cell behaviors, especially directed Commentary focuses on a relatively understudied aspect of migration. We conclude with a description of new developments laminin biology: how is laminin deposited into the extracellular in the way that laminin deposition is being studied, including matrix? This topic has fascinated researchers for some time, the use of tagged laminin subunits that should allow the particularly considering the diversity of patterns of laminin that visualization of laminin-matrix deposition and assembly by can be visualized in the matrix of cultured cells. We discuss living cells. current ideas of how laminin matrices are assembled, the role of matrix receptors in this process and how laminin-associated proteins modulate matrix deposition. We speculate on the role Key words: Extracellular matrix, Integrins, Matrix receptors Introduction the connective tissue. Laminins play important roles in tissue The laminins are heterotrimeric proteins of the extracellular matrix morphogenesis and homeostasis by regulating tissue architecture, that are composed of a-, b- and g-subunits. Currently, in mouse and cell adhesion, migration and matrix-mediated signaling. For human, genes encoding five a-, three b- and three g-subunits instance, mutations in the subunits of laminin-332 in humans cause have been identified (Fig. 1A). When known splice variants are a blistering disease owing to compromised adhesion of keratinocytes included, these subunits assemble into at least 16 different to the laminin-332-deficient basement membrane of the skin laminin heterotrimers (Aumailley et al., 2005) (Table 1). Laminin (McGowan and Marinkovich, 2000; Miner and Yurchenco, 2004). heterotrimers are relatively large proteins (with molecular masses In mice, knockout of the a5 laminin subunit induces a variety of Journal of Cell Science ranging from 400 to 900 kDa) and exist as cross-shaped molecules developmental defects, including syndactyly and aberrant lung with two or three short arms and one long arm (Fig. 1) (Aumailley septation, whereas mice that lack the b2 laminin subunit suffer et al., 2005; Tunggal et al., 2000; Tzu and Marinkovich, 2008; kidney failure owing to defective glomerular filtration (Miner and Yurchenco et al., 2004). The 16 known members of the laminin Yurchenco, 2004). Examples of laminin-mediated signaling come family exhibit some tissue specificity and their expression is often from some of our studies, in which we have demonstrated that developmentally regulated (Aumailley et al., 2005; Tunggal et al., laminin-332 and laminin-311 activate extracellular signal-regulated 2000; Tzu and Marinkovich, 2008; Yurchenco et al., 2004). kinases (ERKs) through modulation of the function of either In keeping with the current trend of rationalizing protein integrin or dystroglycan receptors in epithelial cells (Gonzales et al., nomenclature, the laminin family of proteins has recently been 1999; Jones et al., 2005). reclassified in a more intuitive manner (Aumailley et al., 2005). In Analyses of 2D and 3D cell cultures, mouse models and human the old system, a1b1g1 was known as laminin-1, whereas a3b3g2 disease emphasize the functional duality of laminins as key was named laminin-5. In the new naming system, laminin trimers regulators of tissue structure and cell behavior (Aumailley et al., are known purely by their subunit composition (either including or 2005; Tunggal et al., 2000; Tzu and Marinkovich, 2008; Yurchenco omitting the Greek letters) such that laminin-1 is now known as et al., 2004). By contrast, we know much less about the mechanisms laminin-111 and laminin-5 is laminin-332 (Table 1) (Aumailley by which laminins are deposited and organized into the extracellular et al., 2005). matrix. Yet, as we will detail, laminins are deposited in diverse, Laminin trimers are assembled intracellularly. Initially, disulfide- exquisite arrays in the matrices of disparate cultured cells, probably linked dimers of the b- and g-subunits form (Yurchenco et al., 1997); reflecting differences in laminin-matrix functions. In this for this process, a ten-amino-acid region located toward the Commentary, our focus is the complexity of laminin-rich matrices, C-terminus of the laminin coiled-coil domain of the g-subunit and we use this opportunity to speculate on the mechanisms that appears to be crucial (Nomizu et al., 1996; Utani et al., 1994). The determine how laminin molecules are deposited by cells, bg-dimer is retained in the cytoplasm and requires a-subunit particularly the role of cell-surface receptors and laminin-binding incorporation, and therefore trimerization, to drive secretion. In proteins in regulating such deposition. The molecular structure of addition, the a-subunit can be secreted independently as a monomer laminins, which has been described in a number of recent excellent (Yurchenco et al., 1997). reviews, will be discussed only briefly (Aumailley et al., 2005; In both developing and intact tissues, laminins are incorporated Tunggal et al., 2000; Tzu and Marinkovich, 2008; Yurchenco et al., into basement membranes, which separate parenchymal cells from 2004). 4410 Journal of Cell Science 122 (24) A B Key α5 α1 LN domains LG domains α1 α2 α3B L4 domains LE domains β knob β1 β2 LF domains γ1 γ3 Netrin 4 Collagen VII β3 γ2 α α3A α4 α3A 3A β1 γ1 β3 γ2 β1 γ1 Nidogen Nidogen Agrin α3β1 integrin α6β4 integrin? Dystroglycan Dystroglycan? LM 111 LM 332 LM 311 Fig. 1. Laminin subunits and examples of three heterotrimers. (A)The major laminin-subunit splice isoforms, showing some of the prominent, functionally important domains within each of the subunits (see key). (B)Organization of laminin heterotrimers. Laminins 111, 332 and 331 are depicted. Binding sites for those matrix molecules and receptors that are mentioned in the text are indicated on each diagram (red boxes). Laminin structure and domain architecture secretion of the laminin molecule (Amano et al., 2000; Goldfinger There is a large a globular domain (termed LN) at the N-terminus et al., 1998; Matsui et al., 1995; Talts et al., 2000). Loss of the LG4- of the a1, a2, a3B, a5, b1, b2, g1 and g3 laminin subunits, whereas LG5 domain impacts the function of the laminin heterotrimer, at least this domain is absent from the N-terminus of the a3A, a4 and g2 in the case of laminin-332, in which processing has been reported to laminin subunits (Fig. 1A). For this reason, the former subunits modify the molecule from one that promotes migration to one that have been termed ‘full length’ whereas some authors have called supports stable adhesion (Goldfinger et al., 1998; Tran et al., 2008). the latter ‘truncated’ (Kallunki et al., 1992); here, we will term them Moreover, it is possible that the cleaved LG4-LG5 fragment, under ‘headless’ to avoid confusion with proteolytically processed forms. circumstances in which it is retained in tissue, stimulates migration All laminin subunits contain tandem repeats of laminin-type independently of the mature laminin-332 molecule (Tran et al., 2008). epidermal growth factor-like (LE) domains (Fig. 1A). Globular domains are interspersed among the LE domains: two (L4a and Deposition of laminin heterotrimers: the importance of Journal of Cell Science L4b) in the full-length a-subunits, one domain (LF) in the b1 and b2 patterning subunits, and one (L4) in the g-subunits (Fig. 1A). In each subunit, Despite their relatively uniform structure, laminin heterotrimers are the final LE repeats are followed by an a-helical domain. The deposited into diverse arrays or patterns in the extracellular matrix a-helical domains of the three subunits wind around each other to of cultured cells. We speculate that these laminin-deposition patterns produce a trimeric, coiled-coil structure (Beck et al., 1990). In all reflect differences in laminin-matrix functions and/or that they three b-subunits, this domain is interrupted by a short stretch of represent different stages in matrix formation. There are correlative amino acids termed the b-knob (Beck et al., 1990). The coiled-coil domain is probably important for orienting the large globular domain at the C-terminus of the a-subunit, facilitating its accessibility for Table 1. The subunit composition of laminin heterotrimers cell binding via integrins and other cell-surface receptors, including Former Subunit Current the syndecans and dystroglycan, as well as binding to other matrix designation composition designation proteins (Timpl et al., 2000) (Fig. 1B). For example, Kunneken Laminin 1 a1b1g1 LM 111 and colleagues have demonstrated that the coiled-coil domain and Laminin 2 a2b1g1 LM 211 heterotrimerization are required for the interaction of 3 1 integrin Laminin 3 a1b2g1 LM 121 a b Laminin 4 a2b2g1 LM 221 with laminin-332 (Kunneken et al., 2004). Laminin 5 or 5A a3Ab3g2 LM 332 or 3A32 The coiled-coil of the a laminin subunits is followed by a globular Laminin 5B a3Bb3g2 LM 3B32 C-terminus that can be divided into five LG domains (LG1-LG5) Laminin 6 or 6A a3Ab1g1 LM 311 or 3A11 with LG1-3 and LG4-5 forming functionally and structurally distinct Laminin 7 or 7A a3Ab2g1 LM 321 or 3A21 Laminin 8 a4b1g1 LM 411 subdomains (Fig. 1). A hypothetical model constructed by Tisi and Laminin 9 a4b2g1 LM 421 colleagues predicts that the LG1-3 domain has a cloverleaf shape, Laminin 10 a5b1g1 LM 511 with the coiled-coil rod domain of the trimer contacting this region Laminin 11 a5b2g1 LM 521 (Tisi et al., 2000).
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