Review
Bridging structure with function: Structural, regulatory, and developmental role of laminins

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Abstract

The basement membrane is a highly intricate and organized portion of the extracellular matrix that interfaces with a variety of cell types including epithelial, endothelial, muscle, nerve, and fat cells. The laminin family of glycoproteins is a major constituent of the basement membrane. The 16 known laminin isoforms are formed from combinations of α, β, and γ chains, with each chain containing specific domains capable of interacting with cellular receptors such as integrins and other extracellular ligands. In addition to its role in the assembly and architectural integrity of the basement membrane, laminins interact with cells to influence proliferation, differentiation, adhesion, and migration, processes activated in normal and pathologic states. In vitro these functions are regulated by the post-translational modifications of the individual laminin chains. In vivo laminin knockout mouse studies have been particularly instructive in defining the function of specific laminins in mammalian development and have also highlighted its role as a key component of the basement membrane. In this review, we will define how laminin structure complements function and explore its role in both normal and pathologic processes.

Introduction

The basement membrane (BM) is a complex and highly organized yet dynamic matrix of extracellular material that interfaces with epithelial, endothelial, nerve, fat and muscle cells to provide mechanical support and stability, structural compartmentalization, regulation of cellular activities, and a physical reservoir for cellular growth factors. Basement membranes are specialized for different tissue types but have a basic cross-sectional structure divided into the lamina lucida, lamina densa, and the sublamina densa. The lamina densa which defines the electron dense region of the basement membrane, is comprised predominantly of polymeric networks of collagen and laminin integrated by crosslinkers such as nidogen and perlecan (Ghohestani, Li, Rousselle, & Uitto, 2001). The laminin family of glycoproteins, first discovered as a product of mouse Engelbreth-Holm-Swarm sarcoma (EHS) cells almost three decades ago (Timpl et al., 1979), play a significant role in basement membrane assembly, architecture, and regulation of cellular differentiation, adhesion, and migration. This review will serve to explore the relationship between laminin structure and function, including its role in pathologic processes, from the molecular to the organismal level.

Section snippets

Laminin evolution

Laminins exhibit cross-species similarities in domain sequence. Similar to other basement membrane constituents, laminins are evolutionarily ancient and conserved gene products found in both vertebrates and invertebrates. It is thought that the present day family of laminins arose a single laminin gene, similar to the one found in Hydra vulgaris, through a series of gene duplications and modifications. Laminin α and β chains from Hydra have been cloned and show much sequence similarities to

Family of laminin proteins

Laminins are extracellular heterotrimeric glycoproteins composed of various combinations of α, β, and γ chains (Fig. 1). These large molecules are 400–900 kDa in weight and exhibit a cross shape. To date, five α, four β, and three γ chains (Miner & Yurchenco, 2004), as well as chain splice variants, have been identified to create 16 known laminins (laminins 1–15) in mammals (Aumailley et al., 2005) (Table 1). The number of combinations that can be created from the three chains exceeds the number

Laminins in promoting basement membrane assembly and tissue integrity

Laminins play a prominent role in providing structure to the ECM and anchorage for cells to the basement membrane. Those laminins containing full-length chains in all short arms are capable of polymerization. According to the three-arm interaction model, the three N terminals short arms are believed to interact with the N-terminal short arms of other laminins to produce a lattice-type supramolecular network (Cheng et al., 1997). N-terminal bonding is calcium dependent (Miner & Yurchenco, 2004).

Interactions of laminins with cells

The major cell surface receptors for laminins include integrins and nonintegrin molecules. At least eight integrins are known to interact with laminins (Givant-Horwitz, Davidson, & Reich, 2005) including α1β1, α2β1, α5ν1, α3β1, α6β1, α6β4, αvβ3, αvβ5, and α7β1 (Burkin & Kaufman, 1999; Tzu, Li, & Marinkovich, 2005). Each integrin recognize particular sequences within the laminin α chain and thus binds only to specific set of laminins. The recognition/binding site on the integrin receptor is

Laminin processing

As mentioned previously, laminin molecules can undergo multiple post-translational modifications before reaching its final form. How these heterotrimeric molecules are processed affects the dynamics of cellular movement. Processing of each of the three chains by specific enzymes has been reported (Fig. 2), with specific effects on the interacting cell. These studies have mostly focused on laminin-332 processing.

The laminin-332 α3 chain can be processed at both C and N terminals. C-terminal

Laminins and cell migration

The ECM provides critical signals to interfacing cells to direct the dynamics of cellular motion. For some time, there appeared to be contradictory data on effects of laminin-332 on cellular motility (Goldfinger, Stack, & Jones, 1998). Certain cell lines were known to produce a laminin-332 matrix which promoted migration (Zhang & Kramer, 1996) whereas other cell lines produced laminin-332 which promoted hemidesmosome formation (Baker et al., 1996; O’Toole, Marinkovich, Hoeffler, Furthmayr, &

Wound healing and tumor invasion

Given the role of laminin-332 in cell migration, it is not surprising that laminin-332 is implicated in processes such as wound healing and tumor invasion. Interestingly, keratinocytes activated at the leading edges of wounds are found to express high levels of unprocessed laminin-332 α3 chains, while other quiescent keratinocytes are found to express processed laminin α3 chains. In vitro studies demonstrate that these leading keratinocytes deposit the unprocessed laminin-332 at the rear of the

Tissue distribution of laminin isoforms

Expression patterns of laminin isoforms are regulated both temporally and spatially during development. This results in a specific distribution of laminin isoforms within an organism at any given time. Regulation of α chain expression is an important determinant of the laminin isoform found in a tissue. The α1 chain, found in laminin 1 (111) and 3 (121), is heavily expressed in epithelial cells during early embryogenesis. Its expression becomes more restricted as the organism develops and is

Early embryogenesis

Knockout mouse models have imparted valuable information on the critical role of laminins in development. Through such studies, laminins-111 and 511 have been found to assume essential roles during embryonic development. Laminin-111 is highly expressed during early embryogenesis and deletion of any of its subunits results in peri-implantation lethality. γ1 subunit and β1 subunit deletion resulted in the failure of formation of laminins and consequently the blastocyst's visceral and parietal

Conclusions

Much advancement has been made in our understanding of laminin biology in recent years. Laminins are now recognized to be one of the most important basement membrane components, with diverse structural and active regulatory functions that arise from the interactions of its various domains to cellular receptors and other ligands. In vitro and in vivo knockout mouse studies have elucidated key roles of laminins on cellular behavior and embryonic development. Additional studies are still needed to

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