PDGF-A interactions with fibronectin reveal a critical role for heparan sulfate in directed cell migration during Xenopus gastrulation

Abstract

Platelet-derived growth factor (PDGF) signaling is essential for processes involving cell motility and differentiation during embryonic development in a wide variety of organisms including the mouse, frog, zebrafish, and sea urchin. In early Xenopus laevis embryos, PDGF-AA provides guidance cues for the migration of anterior mesendoderm cells as they move across a fibronectin-rich extracellular matrix. The long form of PDGF-A includes a positively charged carboxyl-terminal retention motif that can interact with the extracellular matrix and heparan sulfate proteoglycans (HSPGs). In this study we demonstrate that PDGF-AA binds directly to fibronectin and that this association is greatly enhanced by heparin. The PDGF-AA-fibronectin binding occurs across a broad range of pHs (5.5-9), which is significant because the PDGF-guided migration of Xenopus mesendoderm cells occurs under basic extracellular conditions (pH 8.4). We further demonstrate that endogenous HSPG's are required for the PDGF-AA-guided mesendoderm movement, suggesting an in vivo role for HSPGs in mediating the interaction between PDGF-AA and fibronectin.embryo ͉ embryonic development ͉ mesendoderm ͉ mesoderm

Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma

“…Indeed, VEGF-A, a factor known to bind heparin/HSPGs in a SULF-dependent manner (18,78,79), can directly activate PDGFRα (80). Furthermore, we observed a slight but consistent decrease in the total levels of PDGFRα.…”

“…Furthermore, Sulf2 expression is increased in many PDGFB-driven tumors regardless of the insertion site (77). Finally, PDGFs interact with HSPGs, and this interaction is influenced by 6-O-sulfation (18,78,79).…”

“…Present on the cell surface and in the ECM, HSPGs play a key role in a number of biological processes based on their ability to bind and regulate the activity of diverse molecules including chemokines and growth factors, such as PDGF, VEGF, and FGF, in many tissues, including the brain (18)(19)(20)(21)(22). Indeed, HSPG binding can sequester ligands and decrease signaling, such as with the Wnts, or it can act as a coreceptor and actually promote receptor signaling, such as with FGF2 and VEGF (23)(24)(25).…”

Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix

“…Thus, the presence of a heparin-binding domain within the GFs seems to be necessary, but not sufficient, to provide binding to Fg β15-66 (2) . We and others have shown enhanced binding of GFs to fibronectin in the presence of heparin, although heparin is not the linker between the two molecules (3,4,27). It has been suggested that heparin and heparan sulfate can change the conformation of fibronectin and increase its affinity for GFs (4,27); however, in the case of GF-Fg β15-66 (2) interaction, heparin did not increase GFbinding ability, but rather decreased it (Fig.…”

“…For example, many GFs are able to bind the proteoglycan components of the ECM (2). Moreover, it has recently become more evident that ECM proteins such as fibronectin and vitronectin, which do not contain highly negatively charged sugar chains, bind several GFs (3)(4)(5)(6)(7)(8). In addition to sequestration of GF by ECM components, the ECM also can modulate cosignaling between adhesion and GF receptor systems.…”