Many growth factors and cytokines are present in extracellular matrices and on cell surfaces. These interactions are mainly mediated by proteoglycans. Growth factors and cytokines may bind glycosaminoglycan moiety or core protein of proteoglycans. In vitro studies have demonstrated that the binding with proteoglycans can alter stability, potency, diffusibility, and affinity to their receptors of growth factors and cytokines. It is becoming clearer that the interaction with proteoglycans plays a crucial role in the regulation of growth factors and cytokines in vivo.
A number of lysosomal glycoproteins exist which are membrane associated and do not contain the mannose-6-phosphate lysosomal targeting signal which sorts soluble lysosomal hydrolases to the lysosome in the Golgi apparatus. These include lysosomal acid phosphatase (LAP), which is targeted as a transmembrane protein to the lysosome where it is cleaved to release the soluble enzyme, and a number of lysosomal membrane associated glycoproteins including the homologous families of LAMP-1 and LAMP-2 as well as other smaller molecular weight glycoproteins including LIMP II and CD63. The cytoplasmic domain of LAP, LAMP-1 and LIMP II is capable of targeting the ectodomain of non-lysosomal glycopoteins to the lysosome. Except for LIMP II, the lysosomal membrane glycoproteins contain a Gly-Tyr-X-X-hydrophobic amino acid lysosomal targeting motif in their cytoplasmic domains. Studies of LAP, LAMP-1 and LAMP-2 have generated conflicting data as to the biosynthetic targeting pathway of these proteins and, in particular, as to whether it includes the plasma membrane.
F3 is a 135kDa glycoprotein expressed at the surface of cultured neuronal cells and released in soluble form in the culture medium. Its structural properties, mainly derived from biochemical and molecular biology studies, revealed that it belongs to two families of cell interaction molecules: the HNK-1 family and the immunoglobulin supergene family. In particular, F3 is built of two kinds of distinct domains: Immunoglobulin type C2 and Fibronectin type III ones. This association is often found in the case of those surface glycoproteins bearing a predominant axonal localization. Accordingly, F3 expression was mainly restricted to neurites in brain primary cultures and to axon tracts in vivo. The molecule expression was found to be developmentally regulated with a peak in phases of the postnatal development characterized by extensive axonal growth and synaptogenesis. Functionally, we demonstrated its ability to mediate heterophilic interactions between nerve cells and to control key developmental processes as neurite outgrowth. On the basis of the above data we suggest that regulation of F3 gene expression during development is provided of key significance in neural morphogenesis.
Pertussis toxin (PT) is a classic “A-B” toxin produced by Bordetella pertussis; the etiologic agent of whooping cough. Like related A-B toxins, PT is composed of a single, enzymatic A subunit and a receptor-binding, B oligomer composed of five additional subunits. In most A-B toxins complex oligosaccharide sequences on glycolipids serve as host cell receptors for the B pentamer. PT is no exception but, unlike related toxins, PT also uses oligosaccharide sequences on glycoproteins as receptors in host cells. Therefore, although the enzymatic activity of the A subunit is responsible for many of PT's biological effects, the binding of its B pentamer to glycoprotein receptors can also directly alter host cell functions. Moreover, the B pentamer of PT is not composed of five identical subunits. Consequently, unlike related A-B toxins whose B pentamers are composed of identical subunits, PT is capable of recognizing several oli-gosaccharide receptor sequences. This review will summarize investigations directed at identifying host cell receptors for PT and amino acid sequences in the toxin's various carbohydrate recognition domains. Research from several laboratories indicates that PT recognizes sialated and asialo-lactosamine sequences on host cell glycoproteins and glycolipids. More recent work indicates that PT also mimics the oligosaccharide binding activities of the calcium-dependent family of eukaryotic lectins (C-lectins) which includes the selectins. Site-directed mutagenesis techniques and synthetic peptides derived from amino acid sequences in the B pentamer of PT identify regions in two of the five subunits that are probably important for coordinating carbohydrate binding.