Heparan Sulfate Acts As a Bone Morphogenetic Protein Coreceptor by Facilitating Ligand-induced Receptor Hetero-oligomerization

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2010 Sep 24

PMID 20861306

Citations 60

Authors

Wan-Jong Kuo

Michelle A Digman

Arthur D Lander

Affiliations

Soon will be listed here.

Abstract

Cell surface heparan sulfate (HS) not only binds several major classes of growth factors but also sometimes potentiates their activities--an effect usually termed "coreception." A view that coreception is due to the stabilization of growth factor-receptor interactions has emerged primarily from studies of the fibroblast growth factors (FGFs). Recent in vivo studies have strongly suggested that HS also plays an important role in regulating signaling by the bone morphogenetic proteins (BMPs). Here, we provide evidence that the mechanism of coreception for BMPs is markedly different from that established for FGFs. First, we demonstrate a direct, stimulatory role for cell surface HS in the immediate signaling activities of BMP2 and BMP4, and we provide evidence that HS-BMP interactions are required for this effect. Next, using several independent assays of ligand binding and receptor assembly, including coimmunoprecipitation, cross-linking, and fluorescence fluctuation microscopy, we show that HS does not affect BMP binding to type I receptor subunits but instead enhances the subsequent recruitment of type II receptor subunits to BMP-type I receptor complexes. This suggests a view of HS as a catalyst of the formation of signaling complexes, rather than as a stabilizer of growth factor binding.

Citing Articles

Dally is not essential for Dpp spreading or internalization but for Dpp stability by antagonizing Tkv-mediated Dpp internalization.

Simon N, Safyan A, Pyrowolakis G, Matsuda S Elife. 2024; 12.

PMID: 38265865 PMC: 10945656. DOI: 10.7554/eLife.86663.

Control of tissue homeostasis by the extracellular matrix: Synthetic heparan sulfate as a promising therapeutic for periodontal health and bone regeneration.

Miguez P, Bash E, Musskopf M, Tuin S, Rivera-Concepcion A, Chapple I Periodontol 2000. 2023; 94(1):510-531.

PMID: 37614159 PMC: 10891305. DOI: 10.1111/prd.12515.

Dynamic Changes in Heparan Sulfate Nanostructure in Human Pluripotent Stem Cell Differentiation.

Al Mahbuba D, Masuko S, Wang S, Syangtan D, Kang J, Song Y ACS Nano. 2023; 17(8):7207-7218.

PMID: 37042659 PMC: 11439449. DOI: 10.1021/acsnano.2c10072.

Delivery of bone morphogenetic protein-2 by crosslinking heparin to nile tilapia skin collagen for promotion of rat calvaria bone defect repair.

Ma L, Fu L, Gu C, Wang H, Yu Z, Gao X Prog Biomater. 2022; 12(1):61-73.

PMID: 36495399 PMC: 9958213. DOI: 10.1007/s40204-022-00213-7.

Coreceptor functions of cell surface heparan sulfate proteoglycans.

Hayashida K, Aquino R, Park P Am J Physiol Cell Physiol. 2022; 322(5):C896-C912.

PMID: 35319900 PMC: 9109798. DOI: 10.1152/ajpcell.00050.2022.

References

Powell A, Yates E, Fernig D, Turnbull J . Interactions of heparin/heparan sulfate with proteins: appraisal of structural factors and experimental approaches. Glycobiology. 2004; 14(4):17R-30R. DOI: 10.1093/glycob/cwh051. View

Fisher M, Li Y, Seghatoleslami M, Dealy C, Kosher R . Heparan sulfate proteoglycans including syndecan-3 modulate BMP activity during limb cartilage differentiation. Matrix Biol. 2005; 25(1):27-39. DOI: 10.1016/j.matbio.2005.07.008. View

Ibrahimi O, Zhang F, Hrstka S, Mohammadi M, Linhardt R . Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry. 2004; 43(16):4724-30. DOI: 10.1021/bi0352320. View

Allendorph G, Vale W, Choe S . Structure of the ternary signaling complex of a TGF-beta superfamily member. Proc Natl Acad Sci U S A. 2006; 103(20):7643-8. PMC: 1456805. DOI: 10.1073/pnas.0602558103. View

Aviezer D, Yayon A . Heparin-dependent binding and autophosphorylation of epidermal growth factor (EGF) receptor by heparin-binding EGF-like growth factor but not by EGF. Proc Natl Acad Sci U S A. 1994; 91(25):12173-7. PMC: 45399. DOI: 10.1073/pnas.91.25.12173. View

Schlessinger J, Plotnikov A, Ibrahimi O, Eliseenkova A, Yeh B, Yayon A . Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell. 2000; 6(3):743-50. DOI: 10.1016/s1097-2765(00)00073-3. View

Plotnikov A, Schlessinger J, Hubbard S, Mohammadi M . Structural basis for FGF receptor dimerization and activation. Cell. 1999; 98(5):641-50. DOI: 10.1016/s0092-8674(00)80051-3. View

Kirkbride K, Townsend T, Bruinsma M, Barnett J, Blobe G . Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor. J Biol Chem. 2008; 283(12):7628-37. DOI: 10.1074/jbc.M704883200. View

Freeman S, Moore W, Guiral E, Holme A, Turnbull J, Pownall M . Extracellular regulation of developmental cell signaling by XtSulf1. Dev Biol. 2008; 320(2):436-45. DOI: 10.1016/j.ydbio.2008.05.554. View

10.

Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis Y, Knaus P . Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell. 2000; 11(3):1023-35. PMC: 14828. DOI: 10.1091/mbc.11.3.1023. View

11.

Pantoliano M, Horlick R, Springer B, Van Dyk D, Tobery T, Wetmore D . Multivalent ligand-receptor binding interactions in the fibroblast growth factor system produce a cooperative growth factor and heparin mechanism for receptor dimerization. Biochemistry. 1994; 33(34):10229-48. DOI: 10.1021/bi00200a003. View

12.

Krufka A, Guimond S, Rapraeger A . Two hierarchies of FGF-2 signaling in heparin: mitogenic stimulation and high-affinity binding/receptor transphosphorylation. Biochemistry. 1996; 35(34):11131-41. DOI: 10.1021/bi960125+. View

13.

Liu F, Ventura F, Doody J, Massague J . Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol. 1995; 15(7):3479-86. PMC: 230584. DOI: 10.1128/MCB.15.7.3479. View

14.

Serpe M, Umulis D, Ralston A, Chen J, Olson D, Avanesov A . The BMP-binding protein Crossveinless 2 is a short-range, concentration-dependent, biphasic modulator of BMP signaling in Drosophila. Dev Cell. 2008; 14(6):940-53. PMC: 2488203. DOI: 10.1016/j.devcel.2008.03.023. View

15.

Kirkbride K, Ray B, Blobe G . Cell-surface co-receptors: emerging roles in signaling and human disease. Trends Biochem Sci. 2005; 30(11):611-21. DOI: 10.1016/j.tibs.2005.09.003. View

16.

Hashimoto O, Nakamura T, Shoji H, Shimasaki S, Hayashi Y, Sugino H . A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells. Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate. J Biol Chem. 1997; 272(21):13835-42. DOI: 10.1074/jbc.272.21.13835. View

17.

Paralkar V, HAMMONDS R, Reddi A . Identification and characterization of cellular binding proteins (receptors) for recombinant human bone morphogenetic protein 2B, an initiator of bone differentiation cascade. Proc Natl Acad Sci U S A. 1991; 88(8):3397-401. PMC: 51454. DOI: 10.1073/pnas.88.8.3397. View

18.

Lemmon M, Dikic I, Ladbury J, Pinchasi D, Huang J, Jaye M . Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell. 1994; 79(6):1015-24. DOI: 10.1016/0092-8674(94)90032-9. View

19.

Bernfield M, Gotte M, Park P, Reizes O, Fitzgerald M, Lincecum J . Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 2000; 68:729-77. DOI: 10.1146/annurev.biochem.68.1.729. View

20.

Natsume T, Tomita S, Iemura S, Kinto N, Yamaguchi A, Ueno N . Interaction between soluble type I receptor for bone morphogenetic protein and bone morphogenetic protein-4. J Biol Chem. 1997; 272(17):11535-40. DOI: 10.1074/jbc.272.17.11535. View