Biomedical subjects

A van der Flier

Publications and source records attributed to A van der Flier.

6 recordsLinked to original sources

PubMed2001

Structural and functional aspects of filamins.

Filamins are a family of high molecular mass cytoskeletal proteins that organize filamentous actin in networks and stress fibers. Over the past few years it has become clear that filamins anchor various transmembrane proteins to the actin cytoskeleton and provide a scaffold for a wide range of cytoplasmic signaling proteins. The recent cloning of three human filamins and studies on filamin orthologues from chicken and Drosophila revealed unexpected complexity of the filamin family, the biological implications of which have just started to be addressed. Expression of dysfunctional filamin-A leads to the genetic disorder of ventricular heterotopia and gives reason to expect that abnormalities in the other isogenes may also be connected with human disease. In this review aspects of filamin structure, its splice variants, binding partners and biological function will be discussed.

Actins↗

PubMed2001

Function and interactions of integrins.

Integrins are heterodimeric cell adhesion molecules that link the extracellular matrix to the cytoskeleton. The integrin family in man comprises 24 members, which are the result of different combinations of 1 of 18 alpha- and 1 of 8 beta-subunits. Alternative splicing of mRNA of some alpha- and beta-subunits and postranslational modifications of integrin subunits further increase the diversity of the integrin family. In their capacity as adhesion receptors that organize the cytoskeleton, integrins play an important role in controlling various steps in the signaling pathways that regulate processes as diverse as proliferation, differentiation, apoptosis, and cell migration. The intracellular signals that lead to these effects may be transduced via cytoplasmic components, which have been identified as integrin-binding proteins in yeast two-hybrid screens and which could mediate the coupling of integrins to intracellular signaling pathways. In this review an overview is given of the function and ligand-binding properties of integrins as well as of proteins that associate with integrins and may play a role in their signaling function.

Animals↗

PubMed1999

Secondary reduction of alpha7B integrin in laminin alpha2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle.

The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The alpha7beta1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be involved in myogenic differentiation and migration processes. The main binding partners of the alpha7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Targeted deletion of the gene for the alpha7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the alpha7B and beta1D integrin subunits, in normal human skeletal muscle, as well as in various forms of muscular dystrophy. In normal human skeletal muscle the expression of the alpha7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the beta1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of alpha7B integrin was significantly reduced at the sarcolemma in six patients with laminin alpha2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin alpha2 chain expressed. In contrast, the expression of the laminin alpha2 chain was not altered in the skeletal muscle of the alpha7 knock-out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha7 integrin subunit and that of the laminin alpha2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha7B was upregulated irrespective of the level of dystrophin expression as shown by a strong sarcolemmal staining pattern even in young boys (age <2 years). The expression of the beta1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of beta1D integrin was significantly reduced in the alpha7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha7B in laminin alpha2 chain deficiency defines a biochemical change in the composition of the plasma membrane resulting from a primary protein deficiency in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in alpha7 deficient mice, implies that the alpha7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.

Adolescent↗

PubMed1998

Genomic organization of the human alpha 3 integrin subunit gene.

The alpha 3 beta 1 integrin is a receptor for various laminin isoforms and plays an important role in the maintenance of tissue integrity. We have characterized the genomic structure of the complete gene for the human alpha 3 integrin subunit. The gene contains 26 exons spanning a region of 36.3 kb of genomic DNA. Its structure closely resembles that of alpha 6, another of the three integrin alpha-subunits that are part of laminin receptors, except that it lacks the corresponding exon 5A, which encodes an X1 region in the extracellular domain of alpha 6. However, the alpha 3 gene contains the equivalent of an exon 5B for an X2-like region, which in alpha 6 and alpha 7 is present only in certain tissue-specific alternative transcripts. The two A and B cytoplasmic variants of alpha 3, which are common to the three laminin receptor integrin alpha-subunits, are encoded by separate exons.

Alternative Splicing↗

PubMed1997

Spatial and temporal expression of the beta1D integrin during mouse development.

The beta1D protein is a recently characterized isoform of the integrin beta1 subunit that is present in cardiac and skeletal muscles. In this study, we have examined the expression of beta1D in different types of skeletal muscle and in cardiac muscle and studied its distribution during mouse development, using new monoclonal antibodies specific for beta1D. Immunoprecipitation studies revealed that, while beta1A is strongly expressed in proliferating C2C12 myoblasts, beta1D is only expressed after their differentiation to myotubes. In these myotubes, beta1D is associated with different alpha subunits, namely alpha3A, alpha5, alpha7A, or alpha7B. Initially, during embryogenesis, the alpha1A subunit is the only beta1 variant expressed in skeletal and cardiac muscle. The beta1D subunit is first detected in skeletal muscle at E17.5, whereas in cardiac muscle its expression begins around the time of birth. Later the expression of beta1A in skeletal and cardiac muscle becomes restricted to capillary cells, whereas beta1D eventually becomes the only variant expressed in adult cardiac and skeletal muscle cells. The switch from the beta1A to the beta1D subunit in cardiac muscle cells coincides with the expression of alpha7. In adults there is a distinct concentration of beta1D at the myotendinous junctions of muscle fibers and at costameres in both cardiac and skeletal muscle. In addition, beta1D is present at intercalated discs in cardiac muscle and at neuromuscular junctions in skeletal muscle cells. The amount of beta1D in different types of skeletal muscle (fast, slow, and mixed-type) was similar, but cardiac muscle expressed almost five times as much of this protein. We suggest that beta1D plays a role in the maintenance of the cytoarchitecture of mature muscle and in the functional integrity of the muscle cells.

Animals↗

PubMed1995

A novel beta 1 integrin isoform produced by alternative splicing: unique expression in cardiac and skeletal muscle.

The mRNA's of several integrin subunits are alternatively spliced in the region encoding cytoplasmic domains, that may potentially provide alternative integrin-cytoskeleton interactions and transmembrane signaling pathways. We identified a novel cytoplasmic tail variant of the human beta 1 subunit by reverse transcriptase polymerase chain reaction. This fourth beta 1 variant, named beta 1D, is specific for skeletal and cardiac muscle. The determined genomic organization of the 3'-region of the human beta 1 gene reveals that beta 1D is produced by alternative splicing of mRNA. In addition, we show that the expression of beta 1D is developmentally regulated during murine myoblast differentiation, suggesting a role for beta 1D in myogenesis.

Alternative Splicing↗