The interaction of the retina cell surface N-acetylgalactosaminylphosphotransferase with an endogenous proteoglycan ligand results in inhibition of cadherin-mediated adhesion.

Abstract

Abstract.We have previously shown that the binding to cells of a monoclonal antibody directed against the chick neural retina N-acetylgalactosaminylphosphotransferase (GalNAcPTase) results in inhibition of cadherin-mediated adhesion and neurite outgrowth. We hypothesized that the antibody mimics the action of an endogenous ligand. Chondroitin sulfate proteoglycans (CSPGs) are potential ligands because they inhibit adhesion and neurite outgrowth and are present in situ at barriers to neuronal growth. We therefore assayed purified CSPGs for their ability to inhibit homophilic cadherin-mediated adhesion and neurite outgrowth, as well as their ability to bind directly to the GalNAcPTase. A proteoglycan with a 250-kD core protein following removal of chondroitin sulfate chains (250-kD PG) inhibits cadherin-mediated adhesion and neurite outgrowth whether presented as the core protein or as a proteoglycan monomer bearing chondroitin sulfate. A proteoglycan with a 400-kD core protein is not inhibitory in either core protein or monomer form. Treatment of cells with phosphatidylinositol-specific phospholipase C, which removes cell surface GalNAcPTase, abolishes this inhibitory effect. Binding of the 250-kD core protein to cells is competed by the anti-GalNAcPTase antibody 1Bll, suggesting that 1Bll and the 250-kD core protein bind to the same site or in close proximity. Moreover, soluble GalNAcPTase binds to the immobilized 250-kD core protein but not to the immobilized 400-kD core protein. Concomitant with inhibition of cadherin mediated adhesion, binding of the 250-kD core protein to the GalNAcPTase on cells results in the enhanced tyrosine phosphorylation of [3-catenin and the uncoupling of N-cadherin from its association with the cytoskeleton. Moreover, the 250-kD PG is present in embryonic chick retina and brain and is associated with the GalNAcPTase in situ. We conclude that the 250-kD PG is an endogenous ligand for the GalNAcPTase. Binding of the 250-kD PG to the GalNAcPTase initiates a signal cascade, involving the tyrosine phosphorylation of [3-catenin, which alters the association of cadherin with the actin-containing cytoskeleton and thereby inhibits adhesion and neurite outgrowth. Regulation of the temporal and spatial expression patterns of each member of the GalNacPTase/ 250-kD PG interactive pair may create opportunities for interaction that influence the course of development through effects on cadherin-based morphogenetic processes.

Thrombospondin-1 Induces Tyrosine Phosphorylation of Adherens Junction Proteins and Regulates an Endothelial Paracellular Pathway

“…While ␤-catenin associates with vascular endothelialcadherin in newly formed and loosely adherent EC junctions, ␥-catenin predominates in tightly confluent EC-EC junctions (Lampugnani et al, 1997). Tyrosine phosphorylation of ZA protein components reduces intercellular EC-EC adhesion (Esser et al, 1998) and disrupts the linkage between cadherin and the actin cytoskeleton (Balsamo et al, 1995;Hazan and Norton, 1998). Tyrosine phosphorylation of ␥-catenin, ␤-catenin, and p120 Cas induced by ligand occupancy of the epidermal growth factor receptor diminishes cell-cell adhesion through disruption of the cadherin-actin cytoskeletal linkage (Hazan and Norton, 1998).…”

N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion and signalling

“…Upon p120 ctn knockdown with siRNA (small interfering RNA), the cadherins are rapidly degraded, probably via ubiquitination (Davis et al, 2003). Also, proteases like MMP (Paradies and Grunwald, 1993), caspase-3 (Hunter et al, 2001) and presenilin (Marambaud et al, 2003) Balsamo et al, 1991Balsamo et al, 1995Guo et al, 2003 Abbreviations used: GATA-4, zinc finger transcription factor recognizes the consensus motif (A/T)GATA(A/G); SOX9, DNA binding SRY box found in SOX family member; Pax6, paired box protein 6; HOXD3, Homeobox D3; HGF, hepatocyte growth factor; EGF, epidermal growth factor; IL-6, interleukin 6; siRNA, small interfering RNA; TF, transcription factor; PKC, protein kinase C; CBP, CREB binding protein; CREB, cyclic AMP response element binding protein.…”

Neurocan developmental expression and function during early avian embryogenesis

“…This observation of non-neural tissue localization of neurocan in meninges, skin, and mesenchyme could point to neural crest cells, transient cell populations which form the meninges, the melanocytes which give rise to the pigment of the skin and hair, and supply mesenchyme to several other developing organs. Neurocan has also been reported to be expressed in the heart and vasculature of avian embryos [7,8], and in mouse T lymphocytes [9] and neoplastic mammary glands [10].…”

“…The neurocan function is elusive [4][5][6][7][8]25]. In vitro studies have shown that neurocan is able to modulate cell-binding, axon guidance and synapse formation during the development of the nervous system via adhesion molecules [3,11,13,27].…”