Disease relevance of LanA

• Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein [1].
• Genetic approaches using Drosophila and Caenorhabditis elegans have demonstrated a role for laminin and a laminin receptor in vivo in axon pathfinding and fasciculation, respectively [4,5] [2].
• Interaction of Bombyx mori nucleopolyhedrovirus BRO-A and host cell protein laminin [3].

High impact information on LanA

• The crumbs protein of Drosophila is an integral membrane protein, with 30 EGF-like and 4 laminin A G domain-like repeats in its extracellular segment, which is expressed on the apical plasma membrane of all ectodermally derived epithelia [4].
• wing blister, a new Drosophila laminin alpha chain required for cell adhesion and migration during embryonic and imaginal development [5].
• In summary, this new laminin alpha chain is essential for embryonic viability and is involved in processes requiring cell migration and cell adhesion [5].
• Most phenotypes are in common with those observed in Drosophila laminin alpha3, 5 mutant embryos and many are in common with those observed in integrin mutations [5].
• The axonemes of elongating spermatids react with antibodies against the Drosophila laminin B1, B2 and laminin A chains [6].

Biological context of LanA

• A novel method of tandemly fused RNA probes showed that developmental increases of laminin mRNAs were primarily associated with periods of morphogenesis, and preceded those of collagen IV, a protein strongly expressed during growth [7].
• Homologs of the G-subdomains of this A chain, which occur in interacting regions of agrin, perlecan, laminin and sex steroid binding protein, may be involved in protein associations [7].
• A Drosophila laminin A chain gene was characterized as a 14 kb genomic nucleotide sequence which encodes an open reading frame of 3712 amino acids in 15 exons [7].
• These phenotypes suggest that laminin A has diverse functions during morphogenesis in Drosophila [8].
• Recent studies ascribed some biological actions of cell adhesion and cell outgrowth to the carboxyl-most 1200 amino acids of vertebrate laminin A chains [9].

Anatomical context of LanA

• Laminin messages appear in newly formed mesoderm and are later prominently expressed in hemocytes, which also synthesize basement membrane collagen IV [7].
• Failure to down-regulate Dystroglycan disrupts apicobasal polarity in the PFC, which includes mislocalization of the extracellular matrix component Laminin [10].
• Dystroglycan is a receptor for multiple extracellular matrix (ECM) molecules such as Laminin, agrin and perlecan, and plays a role in linking the ECM to the actin cytoskeleton; however, how these interactions are regulated and their basic cellular functions are poorly understood [11].
• An established Drosophila neuronal cell line (BG2-c6) proved to be useful to analyze laminin-mediated cell spreading and signal transduction [Takagi et al. (2000) Biochem Biophys Res Commun 270:482-487] [12].
• Northern and Western blot analyses of skin and lung epithelial cells demonstrated the tissue-specific expression of the laminin alpha 3A and alpha 3B isoforms, and in situ hybridization on mouse embryos revealed a focal localization of alpha 3B in areas of the central nervous system [13].

Associations of LanA with chemical compounds

• Phenotypic similarities suggest that laminin A is a potential ligand for this integrin, at least in some tissues [14].
• Furthermore, laminin-dependent BG2-c6 cell spreading was inhibited by heparin [12].
• Its murine counterpart carries the sequence SIKVAV by which the interaction of laminin and cells is mediated [12].
• Two Ciona alpha chains cluster in laminin-binding clade and the remaining chain clusters in the clade that binds the RGD tripeptide sequence [15].
• This proteoglycan-like glycoprotein differs substantially from corresponding proteoglycans found in vertebrate basement membranes, in contrast to Drosophila basement membrane laminin and collagen IV which have been conserved evolutionarily [16].

Regulatory relationships of LanA

• These data indicate that the Drosophila integrin cascade triggered by the interaction between BG2-c6 and laminin was initiated at the integrin cluster with tyrosine-phosphorylated proteins, similar to the observations in vertebrate cells [17].

Other interactions of LanA

• The role of cell adhesion molecules in Drosophila heart morphogenesis: faint sausage, shotgun/DE-cadherin, and laminin A are required for discrete stages in heart development [18].
• Drosophila doubly heterozygous for slit and the genes encoding the integrin ligands Laminin A and Tiggrin reveal similar errors in midline axon guidance [19].
• Furthermore, Dg depends on Pcan but not on Laminin A for its localization in the basal-cell membrane, and the two proteins bind in vitro [20].
• The expression of several additional interactors--viking (vkg), Cg25, and laminin-alpha (LanA)-is affected only in a nonautonomous manner [21].
• Absence of PS integrins or laminin A affects extracellular adhesion, but not intracellular assembly, of hemiadherens and neuromuscular junctions in Drosophila embryos [22].

Analytical, diagnostic and therapeutic context of LanA

• Developmental analyses were undertaken using light and electron microscopy of wild-type and bs wings as well as confocal microscopy of phalloidin- and laminin-stained preparations. bs defects were first seen early in the prepupal period with the failure of apposition of dorsal and ventral wing epithelia [23].
• Previously, an overlapping set of dodecapeptides that covered a region of the murine laminin alpha1 chain similar to recalphaS had been synthesized and tested for cell culture support properties (Nomizu, M., Kim, W. H., Yamamura, K., Utani, A., Otaka, A., Roller, P. P., Kleinman, H. K., and Yamada, Y. (1995) J. Biol. Chem. 270, 20583-20590) [24].
• Sequence analysis of the cDNA for the alpha 3B predicts a polypeptide of 2541 amino acids (279,510 Da) comprising a truncated short arm and a carboxyl-terminal long arm common to the laminin alpha chains identified thus far [13].
• Assembly of Drosophila laminin alpha, beta and gamma chains was analyzed by immunoprecipitation of the lysate from metabolically radiolabeled Kc 167 cells with chain-specific antibodies followed by two dimensional electrophoresis in which non-reducing and reducing SDS gel electrophoresis are combined [25].

References