Defective Laminin 5 Processing in Cylindroma Cells

Tunggal, Lucy; Ravaux, Juliette; Pesch, Monika; Smola, Hans; Krieg, Thomas; Gaill, Françoise; Sasaki, Takako; Timpl, Rupert; Mauch, Cornelia; Aumailley, Monique

doi:10.1016/s0002-9440(10)64865-1

Cited by 50 publications

(40 citation statements)

References 38 publications

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“…Post-translational proteolytic cleavage of several of the proteins modifies their functions and is, therefore, an important regulatory mechanism. For example, the shedding of the transmembrane collagen XVII from keratinocyte surfaces (48) or cleavage of laminin 5 arms influences cell adhesion and migration (10,38). Additionally, as shown in the present study, extracellular processing of procollagen VII to collagen is a prerequisite for correct polymerization of the anchoring fibrils.…”

Section: Discussionsupporting

confidence: 54%

“…The cleavage of the ␥2 chain drives deposition of laminin 5 into the extracellular matrix and sustains cell adhesion (10). In concert, malignant cells with high migratory activity do not process laminin 5 completely (37), and in a cylindroma tumor model, abnormal processing of both chains was associated with striking structural abnormalities of the basement membrane (38).…”

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confidence: 99%

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Proteinases of the Bone Morphogenetic Protein-1 Family Convert Procollagen VII to Mature Anchoring Fibril Collagen

Rattenholl¹,

Pappano²,

Koch³

et al. 2002

Journal of Biological Chemistry

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109

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Collagen VII is the major structural component of the anchoring fibrils at the dermal-epidermal junction in the skin. It is secreted by keratinocytes as a precursor, procollagen VII, and processed into mature collagen during polymerization of the anchoring fibrils. We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the Cterminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA2DTAG within the NC-2 domain. Mammalian tolloid-like (mTLL)-1 and -2, two other proteases of the astacin enzyme family, were able to process procollagen VII at the same site in vitro. Immunohistochemical and genetic evidence supported the involvement of these enzymes in cleaving type VII procollagen in vivo. Both BMP-1 and mTLL-1 are expressed in the skin and in cultured cutaneous cells. A naturally occurring deletion in the human COL7A1 gene, 8523del14, which is associated with dystrophic epidermolysis bullosa and eliminates the BMP-1 consensus sequence, abolished processing of procollagen VII, and in mutant skin procollagen VII accumulated at the dermal-epidermal junction. On the other hand, deficiency of BMP-1 in the skin of knockout mouse embryos did not prevent processing of procollagen VII to mature collagen, suggesting that mTLL-1 and/or mTLL-2 can substitute for BMP-1 in the processing of procollagen VII in situ.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

Proteinases of the Bone Morphogenetic Protein-1 Family Convert Procollagen VII to Mature Anchoring Fibril Collagen

Rattenholl¹,

Pappano²,

Koch³

et al. 2002

Journal of Biological Chemistry

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109

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“…5A). Processing of laminin 5, which is needed for its integration in the basement membrane (25)(26)(27) was not altered in JEB keratinocytes, excluding the possibility that the scattered deposition of laminin 5 was caused by its deficient cleavage (not shown).…”

Section: Abnormal Matrix Deposition and Motility Of Jebmentioning

confidence: 92%

C-terminal Truncation Impairs Glycosylation of Transmembrane Collagen XVII and Leads to Intracellular Accumulation

Franzke

Has

Schulte

et al. 2006

Journal of Biological Chemistry

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Collagen XVII, a type II transmembrane protein in hemidesmosomes, is involved in the anchorage of stratified epithelia to the underlying mesenchyme. Its functions are regulated by ectodomain shedding, and its genetic defects lead to epidermal detachment in junctional epidermolysis bullosa (JEB), a heritable skin fragility syndrome, but the molecular disease mechanisms remain elusive. Here we used a spontaneously occurring homozygous COL17A1 deletion mutant in JEB to discern glycosylation of collagen XVII. The mutation truncated the distal ectodomain and positioned the only N-glycosylation site 34 amino acids from the newly formed C terminus, which impaired efficient N-glycosylation. Immunofluorescence staining of authentic JEB keratinocytes and of COS-7 cells transfected with the mutant indicated intracellular accumulation of collagen XVII precursor molecules. Cell surface biotinylation and quantification of ectodomain shedding demonstrated that only about 15% of the truncated collagen XVII reached the cell surface. The cell surface-associated molecules were N-glycosylated in a normal manner, in contrast to the molecules retained within the cells, indicating that N-glycosylation of the ectodomain is required for targeting of collagen XVII to the plasma membrane and that reduced accessibility of the N-glycosylation site negatively regulates this process. Functional consequences of the strong reduction of collagen XVII on the cell surface included scattered deposition of cell adhesion molecule laminin 5 into the extracellular environment and, as a consequence of faulty collagen XVII-laminin ligand interactions, aberrant motility of the mutant cells.Collagen XVII belongs to the family of collagenous transmembrane proteins, which function both as cell membrane receptors and as extracellular matrix components and are involved in a broad spectrum of biological events, ranging from cell adhesion to host defense (1). The group members typically are trimers of identical polypeptides, ␣-chains, which contain an N-terminal intracellular domain, a single transmembrane stretch, and a large extracellular C terminus with one or more collagenous subdomains, i.e. a structure characteristic of type II transmembrane proteins. The ectodomain is shed from the cell surface by metalloproteinases of the ADAM (a disintegrin and metalloprotease domain) family to yield a shorter form of the molecule, which remains stable in the extracellular space after the release (2). As a component of the hemidesmosomes, collagen XVII is involved in the anchorage of stratified epithelia in the skin, the mucous membranes, or the eye to the underlying mesenchyme.Mutations in the collagen XVII gene, COL17A, cause JEB, a genodermatosis characterized by mechanically induced detachment of the epidermis from the dermis. To date, over 30 different COL17A1 mutations have been reported (Human Gene Mutation Database, Cardiff University; Refs. 3 and 4). Most are null mutations resulting in premature termination codons and, subsequently, in nonsense-mediated mRNA d...

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“…30,31 The major ECM ligand for NHKs is laminin 5, which undergoes a series of processing steps critical for its maturation, deposition, and function. [32][33][34] The processing of soluble laminin 5 was examined by immunoblotting of the culture media of NHKs and C17 Ϫ/Ϫ keratinocytes. Both types of media contained the semiprocessed (165 kd) ␣3A chain (Figure 7a), the unprocessed (155 kd), and processed (105 kd) forms of the ␥2 chain (Figure 7b) and the 140-kd ␤3 chain (Figure 7c).…”

Section: C17 ϫ/ϫ Keratinocytes Do Not Correctly Organize Lamininmentioning

confidence: 99%

Keratinocytes from Patients Lacking Collagen XVII Display a Migratory Phenotype

Tasanen

Tunggal

Chometon

et al. 2004

The American Journal of Pathology

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115

105

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Acquired or inherited junctional epidermolysis bullosa are skin diseases characterized by a separation between the epidermis and the dermis. In inherited nonlethal junctional epidermolysis bullosa, genetic analysis has identified mutations in the COL17A1 gene coding for the transmembrane collagen XVII whereas patients with acquired diseases have autoantibodies against this protein. This suggests that collagen XVII participates in the adhesion of basal keratinocytes to the extracellular matrix. To test this hypothesis, we studied the behavior of keratinocytes with null mutations in the COL17A1 gene. Initial adhesion of mutant cells to laminin 5 was comparable to controls and similarly dependent on ␣3␤1 integrins. The spreading of mutant cells was, however, enhanced, suggesting a propensity to migrate, which was confirmed by migration assays. In addition, laminin 5 deposited by collagen XVII-deficient keratinocytes was scattered and poorly organized , suggesting that correct integration of laminin 5 within the matrix requires collagen XVII. Collagen XVII (or BPAG2, 180-kd bullous pemphigoid antigen) is expressed by epithelial cells forming hemidesmosomes (HDs), such as basal keratinocytes in skin or mucosa. HDs are multiprotein complexes connecting the intracellular keratin network to anchoring filaments and fibrils located in the basement membrane (BM) and the upper dermis, respectively.1 Collagen XVII is expressed as a transmembrane full-length entity that is in part converted to an extracellular protein by shedding.2-4 Because the full-length protein is anchored in a type II orientation in the plasma membrane, its N-terminus is intracellular and the C-terminus, or ectodomain, is extracellular. The intracellular domain of collagen XVII is located in the cytoplasmic plaque of HDs where it colocalizes and interacts with the intracellular tail of the integrin ␤4 subunit, BPAG1 (230-kd bullous pemphigoid antigen) and HD1/plectin, 5 which in turn acts as a molecular bridge to the keratin-based cytoskeleton.1 A further interaction occurs between extracellular stretches adjacent to the transmembrane domains of collagen XVII and integrin ␣6 subunit.

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Defective Laminin 5 Processing in Cylindroma Cells

Cited by 50 publications

References 38 publications

Proteinases of the Bone Morphogenetic Protein-1 Family Convert Procollagen VII to Mature Anchoring Fibril Collagen

Proteinases of the Bone Morphogenetic Protein-1 Family Convert Procollagen VII to Mature Anchoring Fibril Collagen

C-terminal Truncation Impairs Glycosylation of Transmembrane Collagen XVII and Leads to Intracellular Accumulation

Keratinocytes from Patients Lacking Collagen XVII Display a Migratory Phenotype

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