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Control of Growth Factor Networks by Heparan Sulfate Proteoglycans

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Abstract

Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different growth factors may allow for cross regulation. Here we demonstrate, using experiments and computer simulations, that the HB-GFs FGF-2 and heparin-binding EGF-like growth factor (HB-EGF) can cross regulate receptor binding of the other despite having unique receptors. The ability of HSPG to stabilize HB-GF receptor binding is critical for competing growth factors to modulate receptor binding with both enhanced and reduced binding possible depending on this stabilization process. HSPG density and affinity for HB-GF are also critical factors for HB-GF cross regulation. Simulations further reveal that HB-GF can regulate receptor binding of non-HB-GFs such as EGF even when the two proteins share no binding sites when other HB-GF are present within the network. Proliferation studies demonstrate potentiation of HB-EGF-induced growth by FGF-2 indicating that competition networks can alter biological response. Exogenous manipulation of cellular responses to growth factors in complex living systems will require understanding the HSPG-controlled network.

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Acknowledgment

This study was supported by grants from NIH (HL56200 and HL86644).

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA

    Kimberly Forsten-Williams

  2. Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA

    Chia Lin Chu, Jo Ann Buczek-Thomas & Matthew A. Nugent

  3. Department of Ophthalmology and Visual Science, University of Kentucky, Lexington, KY, USA

    Michael Fannon

  4. Department of Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA

    Matthew A. Nugent

  5. Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA

    Matthew A. Nugent

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  1. Kimberly Forsten-Williams
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Corresponding author

Correspondence to Kimberly Forsten-Williams.

Appendix

Appendix

We developed two related models for this work and the equations are listed below. For HB-EGF binding in the “non-receptor-coupling” model:

$$ \frac{{dR_{{\text{H}}} }} {{dt}} = S^{{\text{H}}}_{{\text{R}}} - k^{{{\text{RH}}}}_{{\text{f}}} HR_{{\text{H}}} + k^{{{\text{RH}}}}_{{\text{r}}} C_{{\text{H}}} + k_{{{\text{uc}}}} T_{{\text{H}}} - k_{{\text{c}}} G_{{\text{H}}} R_{{\text{H}}} - k_{{\text{i}}} R_{{\text{H}}} $$
(1)
$$ \frac{{dC_{{\text{H}}} }} {{dt}} = k^{{{\text{RH}}}}_{{\text{f}}} HR_{{\text{H}}} - k^{{{\text{RH}}}}_{{\text{r}}} C_{{\text{H}}} - k_{{\text{c}}} C_{{\text{H}}} C_{{\text{H}}} + 2k_{{{\text{uc}}}} C_{{{\text{2H}}}} + k_{{{\text{uc}}}} T_{{\text{H}}} - k_{{\text{c}}} P_{{\text{H}}} C_{{\text{H}}} - k_{{\text{i}}} C_{{\text{H}}} $$
(2)
$$ \frac{{dC_{{{\text{2H}}}} }} {{dt}} = 0.5k_{{\text{c}}} C_{{\text{H}}} C_{{\text{H}}} - k_{{{\text{uc}}}} C_{{{\text{2H}}}} + k_{{{\text{uc}}}} X_{{\text{H}}} - k_{{\text{c}}} P_{{\text{H}}} C_{{{\text{2H}}}} - k_{{{\text{i*}}}} C_{{{\text{2H}}}} $$
(3)
$$ \frac{{dP_{{\text{H}}} }} {{dt}} = S^{{\text{H}}}_{{\text{P}}} - k^{{{\text{PH}}}}_{{\text{f}}} HP_{{\text{H}}} + k^{{{\text{PH}}}}_{{\text{r}}} G_{{\text{H}}} + k_{{{\text{uc}}}} T_{{\text{H}}} - k_{{\text{c}}} P_{{\text{H}}} C_{{\text{H}}} - k_{{\text{c}}} C_{{2{\text{H}}}} P_{{\text{H}}} + k_{{{\text{uc}}}} X_{{\text{H}}} - k_{{\text{c}}} X_{{\text{H}}} P_{{\text{H}}} + k_{{{\text{uc}}}} T_{{{\text{2H}}}} - k_{{\text{i}}} P_{{\text{H}}} $$
(4)
$$ \frac{{dG_{\rm H} }} {{dt}} = k^{{\rm PH}}_{\rm f} HP_{\rm H} - k^{{\rm PH}}_{\rm r} G_{\rm H} + k_{{\rm uc}} T_{\rm H} - k_{\rm c} G_{\rm H} R_{\rm H} - k_{\rm i} G_{\rm H} $$
(5)
$$ \frac{{dX_{{\text{H}}} }} {{dt}} = k_{{\text{c}}} C_{{2{\text{H}}}} P_{{\text{H}}} - k_{{{\text{uc}}}} X_{{\text{H}}} + k_{{{\text{uc}}}} T_{{{\text{2H}}}} - k_{{\text{c}}} X_{{\text{H}}} P_{{\text{H}}} - k_{{{\text{i*}}}} X_{{\text{H}}} $$
(6)
$$ \frac{{dT_{{\text{H}}} }} {{dt}} = k_{{\text{c}}} G_{{\text{H}}} R_{{\text{H}}} - k_{{{\text{uc}}}} T_{{\text{H}}} + k_{{\text{c}}} P_{{\text{H}}} C_{{\text{H}}} - k_{{{\text{uc}}}} T_{{\text{H}}} - k_{{\text{c}}} T_{{\text{H}}} T_{{\text{H}}} + 2k_{{{\text{uc}}}} T_{{{\text{2H}}}} - k_{{\text{i}}} T_{{\text{H}}} $$
(7)
$$ \frac{{dT_{{{\text{2H}}}} }} {{dt}} = k_{{\text{c}}} X_{{\text{H}}} P_{{\text{H}}} - k_{{{\text{uc}}}} T_{{{\text{2H}}}} + 0.5k_{{\text{c}}} T_{{\text{H}}} T_{{\text{H}}} - k_{{{\text{uc}}}} T_{{{\text{2H}}}} - k_{{{\text{i*}}}} T_{{{\text{2H}}}} $$
(8)
$$ V\frac{{dH}} {{dt}} = - k^{{{\text{RH}}}}_{{\text{f}}} HR_{{\text{H}}} - k^{{{\text{RH}}}}_{{\text{r}}} C_{{\text{H}}} - k^{{{\text{PH}}}}_{{\text{f}}} HP_{{\text{H}}} + k^{{{\text{PH}}}}_{{\text{r}}} G_{{\text{H}}}$$
(9)

Nine additional equations identical in structure are written for FGF-2 binding with H replaced by F

For HSPG common sites:

$$ \frac{{dP^{{\text{c}}} }} {{dt}} = - k^{{{\text{PcF}}}}_{{\text{f}}} FP^{{\text{c}}} + k^{{{\text{PcF}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{F}}} - k^{{{\text{PcH}}}}_{{\text{f}}} HP^{{\text{c}}} + k^{{{\text{PcH}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{H}}} $$
(10)
$$ \frac{{dG^{{\text{c}}}_{{\text{H}}} }} {{dt}} = k^{{{\text{PcH}}}}_{{\text{f}}} HP^{{\text{c}}} - k^{{{\text{PcH}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{H}}} $$
(11)
$$ \frac{{dG^{{\text{c}}}_{{\text{F}}} }} {{dt}} = k^{{{\text{PcF}}}}_{{\text{f}}} FP^{{\text{c}}} - k^{{{\text{PcF}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{F}}} $$
(12)

In the “receptor-coupling” model, HSPG common sites are able to interact with receptors to form higher order complexes. Hence Eqs. (10–12) are replaced by Eqs. (13–15)

$$ \begin{aligned}{} & \frac{{dP_{{\text{c}}} }} {{dt}} = S^{{\text{C}}}_{{\text{P}}} - k^{{{\text{PcF}}}}_{{\text{f}}} FP^{{\text{c}}} + k^{{{\text{PcF}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{F}}} - k^{{{\text{PcH}}}}_{{\text{f}}} HP^{{\text{c}}} + k^{{{\text{PcH}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{H}}} - k_{{\text{c}}} C_{{\text{F}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{\text{F}}} - k_{{\text{c}}} C_{{{\text{2F}}}} P^{{\text{c}}} \\ & + k_{{{\text{uc}}}} X^{{\text{c}}}_{{\text{F}}} - k_{{\text{c}}} X^{{\text{c}}}_{{\text{F}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{2F}}}} - k_{{\text{c}}} X_{{\text{F}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{FF}}}} - k_{{\text{c}}} C_{{\text{H}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{\text{H}}} - k_{{\text{c}}} C_{{{\text{2H}}}} P^{{\text{c}}} \\ & + k_{{{\text{uc}}}} X^{{\text{c}}}_{{\text{H}}} - k_{{\text{c}}} X^{{\text{c}}}_{{\text{H}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{2H}}}} - k_{{\text{c}}} X_{{\text{H}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{HH}}}} - k_{{\text{i}}} P^{{\text{c}}} \\ \end{aligned} $$
(13)
$$ \frac{{dG^{{\text{c}}}_{{\text{H}}} }} {{dt}} = k^{{{\text{PcH}}}}_{{\text{f}}} HP^{{\text{c}}} - k^{{{\text{PcH}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{H}}} - k_{{\text{c}}} G^{{\text{c}}}_{{\text{H}}} R_{{\text{H}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{\text{H}}} - k_{{\text{i}}} G^{{\text{c}}}_{{\text{H}}} $$
(14)
$$ \frac{{dG^{{\text{c}}}_{{\text{F}}} }} {{dt}} = k^{{{\text{PcF}}}}_{{\text{f}}} FP^{{\text{c}}} - k^{{{\text{PcF}}}}_{{\text{r}}} G^{{\text{c}}}_{{\text{F}}} - k_{{\text{c}}} G^{{\text{c}}}_{{\text{F}}} R_{{\text{F}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{\text{F}}} - k_{{\text{i}}} G^{{\text{c}}}_{{\text{F}}} $$
(15)

Plus the addition of:

$$ \frac{{dT^{{\text{c}}}_{{\text{H}}} }} {{dt}} = k_{{\text{c}}} G^{{\text{c}}}_{{\text{H}}} R_{{\text{H}}} - k_{{{\text{uc}}}} T^{{\text{c}}}_{{\text{H}}} + k_{{\text{c}}} P^{{\text{c}}} C_{{\text{H}}} - k_{{{\text{uc}}}} T^{{\text{c}}}_{{\text{H}}} - k_{{\text{c}}} T^{{\text{c}}}_{{\text{H}}} T^{{\text{c}}}_{{\text{H}}} + 2k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{2H}}}} - k_{{\text{c}}} T^{{\text{c}}}_{{\text{H}}} T_{{\text{H}}} + 2k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{HH}}}} - k_{\rm i} T^{{\text{c}}}_{{\text{H}}} $$
(16)
$$ \frac{{dT^{{\text{c}}}_{{{\text{2H}}}} }} {{dt}} = 0.5k_{{\text{c}}} T^{{\text{c}}}_{{\text{H}}} T^{{\text{c}}}_{{\text{H}}} - k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{2H}}}} + k_{{\text{c}}} X^{{\text{c}}}_{{\text{H}}} P^{{\text{c}}} - k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{2H}}}} - k_{{{\text{i*}}}} T^{{\text{c}}}_{{{\text{2H}}}} $$
(17)
$$ \frac{{dT^{{\text{c}}}_{{{\text{HH}}}} }} {{dt}} = k_{{\text{c}}} T^{{\text{c}}}_{{\text{H}}} T_{{\text{H}}} - 3k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{HH}}}} + k_{{\text{c}}} X^{{\text{c}}}_{{\text{H}}} P_{{\text{H}}} - k_{{\text{c}}} X_{{\text{H}}} P^{{\text{c}}} - k_{{{\text{i*}}}} T^{{\text{c}}}_{{{\text{HH}}}} $$
(18)
$$ \frac{{dX^{{\text{c}}}_{{\text{H}}} }} {{dt}} = k_{{\text{c}}} C_{{{\text{2H}}}} P^{{\text{c}}} - k_{{{\text{uc}}}} X^{{\text{c}}}_{{\text{H}}} - k_{{\text{c}}} X^{{\text{c}}}_{{\text{H}}} P_{{\text{H}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{HH}}}} - k_{{\text{c}}} X^{{\text{c}}}_{{\text{H}}} P^{{\text{c}}} + k_{{{\text{uc}}}} T^{{\text{c}}}_{{{\text{2H}}}} - k_{{{\text{i*}}}} X^{{\text{c}}}_{{\text{H}}} $$
(19)

and four additional identical equations for FGF-2 with H replaced by F.

Also, note that additional terms reflecting the interactions of the HSPG common sites with HB-EGF and FGF-2 receptors were added to Eqs. (1–9) and the accompanying FGF-2 equations to balance the system.

The parameter symbols and values are given in Table 2. Unbound receptors (R H, R F ), ligand bound receptors (C H, C F ), receptor–ligand dimers (C 2H, C 2F), unbound ligand-specific proteoglycans (P H, P F), unbound common site proteoglycan (P c), ligand bound proteoglycans (G H, G F, G cH , G cF ), receptor–ligand–proteoglycan complexes (T H, T F, T cH , T cF ), receptor–ligand dimers bound to a proteoglycan site (X H, X F, X cH , X cF ), dimers of receptor–ligand–proteoglycan complexes (T 2H, T 2F, T HH, T cHH , T c2H , T c2F ), and ligand concentration (H, F) form the variables in the system with subscripts H and F representing HB-EGF and FGF-2, respectively. The superscript c indicates HSPG common site.

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Forsten-Williams, K., Chu, C.L., Fannon, M. et al. Control of Growth Factor Networks by Heparan Sulfate Proteoglycans. Ann Biomed Eng 36, 2134–2148 (2008). https://doi.org/10.1007/s10439-008-9575-z

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