Functional studies of one of these novel proteins (LaNt 31) suggest that it plays a role in keratinocyte adhesion, spreading and migration, although the precise mechanisms by which it acts have yet to be defined (Hamill et al., 2009). However, because of their domain name composition and structural similarity to the netrins, we speculate that this LaNts are involved in regulating laminin-network formation through competition or enhancement of LN-LN domain interactions. == Collagen VII == Collagen VII, a component of the anchoring fibrils of the skin, interacts with the 3 subunit of laminin-332 (Chen et al., 1999;Rousselle et al., 1997). Keratinocytes that lack collagen VII do deposit laminin-332 into the basement membrane of skin grafts, indicating that collagen VII is not necessary for deposition of KIAA0538 laminin-332 matrix (Chen et al., 2002). an important role in specifying cell behaviors, especially directed migration. We conclude with a description of new developments in the way that laminin deposition is being studied, including the STING ligand-1 use of tagged laminin subunits that should allow the visualization of laminin-matrix deposition and assembly by living cells. Keywords:Extracellular matrix, Integrins, Matrix receptors == Introduction == The laminins are heterotrimeric proteins of the extracellular matrix that are composed of -, – and -subunits. Currently, in mouse and human, genes encoding five -, three – and three -subunits have been identified (Fig. 1A). When known splice variants are included, these subunits assemble into at least 16 different laminin heterotrimers (Aumailley et al., 2005) (Table 1). Laminin heterotrimers are relatively large proteins (with molecular masses ranging from 400 to 900 kDa) and exist as cross-shaped molecules with two or three short arms and one long arm (Fig. 1) (Aumailley et al., 2005;Tunggal et al., 2000;Tzu and Marinkovich, 2008;Yurchenco et al., 2004). The 16 known members of the laminin family exhibit some tissue specificity and their expression is usually often developmentally regulated (Aumailley et al., 2005;Tunggal et al., 2000;Tzu and Marinkovich, 2008;Yurchenco et al., 2004). == 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) Business of laminin heterotrimers. Laminins 111, 332 and 331 are depicted. Binding sites for those matrix molecules and receptors that are pointed out in the text are indicated on each diagram (red boxes). == Table 1. == The subunit composition of laminin heterotrimers The aged and current designations for the laminin heterotrimers STING ligand-1 are indicated [adapted from (Aumailley et al., 2005)] In keeping with the current pattern of rationalizing protein nomenclature, the laminin family of proteins has recently been reclassified in a more intuitive manner (Aumailley et al., 2005). In the aged system, 111 was known as laminin-1, whereas 332 was named laminin-5. In the new naming system, laminin trimers are known purely by STING ligand-1 their subunit composition (either including or omitting the Greek letters) such that laminin-1 is now known as laminin-111 and laminin-5 is usually laminin-332 (Table 1) (Aumailley et al., 2005). Laminin trimers are assembled intracellularly. Initially, disulfide-linked dimers of the – and -subunits form (Yurchenco et al., 1997); for this process, a ten-amino-acid region located toward the C-terminus of the laminin coiled-coil domain name of the -subunit appears to be crucial (Nomizu et al., 1996;Utani et al., 1994). The -dimer is usually retained in the cytoplasm and STING ligand-1 requires -subunit incorporation, and therefore trimerization, to drive secretion. In addition, the -subunit can be secreted independently as a monomer (Yurchenco et al., 1997). In both developing and intact tissues, laminins are incorporated into basement membranes, which individual parenchymal cells from the connective tissue. Laminins play important functions in tissue morphogenesis and homeostasis by regulating tissue architecture, cell adhesion, migration and matrix-mediated STING ligand-1 signaling. For instance, mutations in the subunits of laminin-332 in humans cause a blistering disease owing to compromised adhesion of keratinocytes to the laminin-332-deficient basement membrane of the skin (McGowan and Marinkovich, 2000;Miner and Yurchenco, 2004). In mice, knockout of the 5 laminin subunit induces a variety of developmental defects, including syndactyly and aberrant lung septation, whereas mice that lack the 2 2 laminin subunit suffer kidney failure owing to defective glomerular filtration (Miner and Yurchenco, 2004). Examples of laminin-mediated signaling come from some of our studies, in which we have exhibited that laminin-332 and laminin-311 activate extracellular signal-regulated kinases (ERKs) through modulation of the function of either integrin or dystroglycan receptors in epithelial cells (Gonzales et al., 1999;Jones et al., 2005). Analyses of 2D and 3D cell cultures, mouse models and human disease emphasize the functional duality of laminins as key regulators of tissue structure and cell behavior (Aumailley et al., 2005;Tunggal et al., 2000;Tzu and Marinkovich, 2008;Yurchenco et al., 2004). By contrast, we know much less about the mechanisms by which laminins are deposited and organized into the extracellular matrix. Yet, as we will detail, laminins are deposited in diverse, exquisite arrays in the matrices of disparate cultured cells, probably reflecting differences in laminin-matrix functions. In this Commentary, our focus is usually.