ReviewBridging structure with function: Structural, regulatory, and developmental role of laminins
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
References (102)
- et al.
Bone morphogenetic protein 1 is an extracellular processing enzyme of the laminin 5 gamma 2 chain
J. Biol. Chem.
(2000) - et al.
A simplified laminin nomenclature
Matrix Biol.
(2005) - et al.
Laminin 5 processing and its integration into the ECM
Matrix Biol.
(2003) - et al.
Membrane type 1 matrix metalloprotease cleaves laminin-10 and promotes prostate cancer cell migration
Neoplasia
(2005) - et al.
Posttranslational modifications and beta/gamma chain associations of human laminin alpha1 and laminin alpha5 chains: Purification of laminin-3 from placenta
Exp. Cell Res.
(2000) - et al.
NC1 domain of type VII collagen binds to the beta3 chain of laminin 5 via a unique subdomain within the fibronectin-like repeats
J. Invest. Dermatol.
(1999) - et al.
Self-assembly of laminin isoforms
J. Biol. Chem.
(1997) - et al.
The human alpha3b is a ‘full-sized’ laminin chain variant with a more widespread tissue expression than the truncated alpha3a
FEBS Lett.
(1997) - et al.
Laminins containing the beta2 chain modulate the precise organization of CNS synapses
Mol. Cell Neurosci.
(2007) - et al.
Expression and biological role of laminin-1
Matrix Biol.
(2003)
Restricted distribution of laminin alpha1 chain in normal adult mouse tissues
Matrix Biol.
Laminin gamma3 chain binds to nidogen and is located in murine basement membranes
J. Biol. Chem.
Molecular organization of the cutaneous basement membrane zone
Clin. Dermatol.
Laminin-induced signaling in tumor cells
Cancer Lett.
Epithelial cell motility on laminin-5: Regulation by matrix assembly, proteolysis, integrins and erbB receptors
Matrix Biol.
Integrin alpha6beta4–erbB2 complex inhibits haptotaxis by up-regulating E-cadherin cell–cell junctions in keratinocytes
J. Biol. Chem.
Laminin-6 is activated by proteolytic processing and regulates cellular adhesion and migration differently from laminin-5
J. Biol. Chem.
The requirement of the glutamic acid residue at the third position from the carboxyl termini of the laminin gamma chains in integrin binding by laminins
J. Biol. Chem.
Molecular cloning and tissue-specific expression of a novel murine laminin gamma3 chain
J. Biol. Chem.
Laminin gamma2-chain fragment circulating level increases in patients with metastatic pancreatic ductal cell adenocarcinomas
Cancer Lett.
Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin gamma 2 chain
J. Biol. Chem.
The anchoring filament protein kalinin is synthesized and secreted as a high molecular weight precursor
J. Biol. Chem.
Defective glomerulogenesis in the absence of laminin alpha5 demonstrates a developmental role for the kidney glomerular basement membrane
Dev. Biol.
Laminin-11
Int. J. Biochem. Cell Biol.
Laminin alpha2 chain-null mutant mice by targeted disruption of the Lama2 gene: A new model of merosin (laminin 2)-deficient congenital muscular dystrophy
FEBS Lett.
Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling
J. Biol. Chem.
Ligation of integrin alpha 3beta 1 by laminin 5 at the wound edge activates Rho-dependent adhesion of leading keratinocytes on collagen
J. Biol. Chem.
Epithelial laminin alpha5 is necessary for distal epithelial cell maturation, VEGF production, and alveolization in the developing murine lung
Dev. Biol.
Laminin alpha 5 is required for lobar septation and visceral pleural basement membrane formation in the developing mouse lung
Dev. Biol.
Laminin-5 inhibits human keratinocyte migration
Exp. Cell Res.
Laminin isoforms in tumor invasion, angiogenesis and metastasis
Semin. Cancer Biol.
Cloning and biological function of laminin in Hydra vulgaris
Dev. Biol.
Short arm region of laminin-5 gamma2 chain: Structure, mechanism of processing and binding to heparin and proteins
J. Mol. Biol.
Integrin beta4 regulates migratory behavior of keratinocytes by determining laminin-332 organization
J. Biol. Chem.
Structural analysis and proteolytic processing of recombinant G domain of mouse laminin alpha2 chain
FEBS Lett.
Structural and functional analysis of the recombinant G domain of the laminin alpha4 chain and its proteolytic processing in tissues
J. Biol. Chem.
Laminin—A glycoprotein from basement membranes
J. Biol. Chem.
Defective laminin 5 processing in cylindroma cells
Am. J. Pathol.
Basement membrane and extracellular matrix molecules in the skin
Mammalian tolloid metalloproteinase, and not matrix metalloprotease 2 or membrane type 1 metalloprotease, processes laminin-5 in keratinocytes and skin
J. Biol. Chem.
An endothelial laminin isoform, laminin 8 (alpha4beta1gamma1), is secreted by blood neutrophils, promotes neutrophil migration and extravasation, and protects neutrophils from apoptosis
Blood
Assembly and tissue functions of early embryonic laminins and netrins
Curr. Opin. Cell Biol.
Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia
Br. J. Dermatol.
Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice
Mol. Cell Biol.
Laminin-5 and hemidesmosomes: Role of the alpha 3 chain subunit in hemidesmosome stability and assembly
J. Cell Sci.
Skin and hair follicle integrity is crucially dependent on beta 1 integrin expression on keratinocytes
EMBO J.
Native chick laminin-4 containing the beta 2 chain (s-laminin) promotes motor axon growth
J. Cell Biol.
The alpha7beta1 integrin in muscle development and disease
Cell Tissue Res.
Human amnion contains a novel laminin variant, laminin 7, which like laminin 6, covalently associates with laminin 5 to promote stable epithelial–stromal attachment
J. Cell Biol.
Form and function: The laminin family of heterotrimers
Dev. Dyn.
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