Diversification of the Structural Determinants of Fibroblast Growth Factor-Heparin Interactions

Abstract

Background: Heparan sulfate (HS) regulates the transport and signaling activities of fibroblast growth factors (FGF). Results: The molecular determinants of the interactions of FGFs and heparin were identified. Conclusion: There are clear molecular specificities determining the interactions of FGFs with the polysaccharide. Significance: The expansion of the FGFs in metazoan evolution parallels the diversification of the specificity of their interactions with heparin.

Chondroitin/dermatan 2-O sulfotransferase potentiates Fgf2 induced cell migration

“…HS proteoglycans and heparin are well studied in this context (Pellegrini et al, 2000) as they promote cell proliferation and ERK1/2 activation (Guimond et al, 1993, Pye and Kumar, 1998, Delehedde et al, 2000. Recent studies have revealed distinct structural features of heparin that allow it to bind to Fgfs with a clear preference for the importance of 2-O sulfation of L-IdoUA (Xu et al, 2012;Jemth et al, 2002). The structural and functional aspects of HS and CS/DS in Fgf mitogenic activity are controversial, as both stimulation and inhibition have been reported (Guimond and Turnbull, 1999;Pye and Kumar, 1998;Fthenou et al, 2009;Yamada and Sugahara, 2008).…”

The nature of the conserved basic amino acid sequences found among 437 heparin binding proteins determined by network analysis

“…41 The approach has been used to determine the HBS for FGF-1, -2, -3, -4, -6, -7, -9, -10, -17, -18 and -20. [41][42][43] The principal example shown in the text is for FGF-1, colloquially termed acidic FGF. The network analysis method described here identifies sequences within this protein that are highly similar to sequences found in other proteins known to bind heparin/HS, see Fig.…”

“…The 'Protect and Label' mass spectrometry performed on FGF-1 identified four heparin binding regions: KKPKLLY (amino acids (aa) 24-30); IKSTETGQYL (aa71-80); ISKKHAEKNWF (aa113-123); and VGLKKNGSCKRGPRTHYGQAILFLPL (aa124-150). 42 The analysis described above identified amino acid sequences within each of the previously identified regions in FGF-1 that interact with HS/heparin (Fig. 1).…”

“…2 with the 'protect and label' mass spectroscopy hits (Table 4). 41,42 Furthermore, validation against FGF-3, -4, -6, -10, -17 and -20 are in ESI. † The above analysis indicates that the conserved amino acid containing sequences that are found in HEPbps form a significant part of the heparin binding regions of a protein.…”

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

“…Alteration of the FGF-7-FGFR2IIIb signaling axis contributes to the oncogenic process by activating intracellular kinase cascades including ERKdependent proliferation and AKT-mediated cell survival in breast cancer cells 37 , and antiFGFR2IIIb antibodies offer a new therapeutic option. 38 Since FGF-7 is one of the most structurally specific FGFs with respect to its requirement for a 3-O-sulfated motif to coordinate ligand-receptor complex assembly 39,40 , we investigated whether 3-OST3A expression may regulate its signaling pathway to trigger the tumor-suppressive effect observed in the lumA-MCF-7 cells. Supporting this assumption, our data show that reinstating 3-OST3A expression in these cells: i) impaired interactions between FGF-7 and HS chains, ii) inhibited proliferative signals via ERK dephosphorylation, and iii) boosted apoptotic signals via AKT dephosphorylation and p38 phosphorylation.…”