Phase separation on cell surface: a mechanism of basic fibroblast growth factor signal transduction with heparan sulphate

Liquid-liquid phase separation (LLPS) driven by weak, multivalent interactions among biomolecules is an important means of cellular compartmentation and plays a central role in cellular processes including stress resistance, RNA processing and other cellular activities. Coordination of the condensates and inner membrane was recently revealed, mediating intracellular processes like cell signalling and cargo trafficking. Intracellular LLPS has been observed extensively in vivo, whereas LLPS in extracellular compartments has not been reported under physiological conditions. Here we show, for the first time, that basic fibroblast growth factor (bFGF) undergoes LLPS on the cell surface by interacting with heparan sulphate proteoglycans (HSPG) and the phase transition is required for effective downstream signalling. The condensation is driven by multivalent interactions between bFGF and sulpho- groups on heparan sulphate (HS), and dimerization and oligomerization of bFGF promote the LLPS process. Compared with free bFGF, phase separated bFGF with HS showed higher thermo stability, providing a potential mechanism for the preservation of bFGF activity. Furthermore, we have found that downstream signalling is triggered by phase separation of a ternary complex formed by bFGF, HSPGs and FGFR on cell surface. Our results revealed a molecular mechanism that HS can serve as a platform to promote extracellular proteins like bFGF to condensate on outer membrane, consequently coordinating the signal transduction activities. This novel finding expands the horizons of phase separation in vivo, providing a new dimension on how HSPG may regulate extracellular protein behaviour and cell signalling.

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Basic fibroblast growth factor: an extracellular mechanotransducer in articular cartilage?

Biochemical Society Transactions ◽

10.1042/bst0340456 ◽

2006 ◽

Vol 34 (3) ◽

pp. 456-457 ◽

Cited By ~ 14

Author(s):

T. Vincent ◽

J. Saklatvala

Keyword(s):

Articular Cartilage ◽

Growth Factor ◽

Cell Surface ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Articular Chondrocytes ◽

Heparan Sulphate ◽

Mechanical Stimuli ◽

Fibroblast Growth ◽

Extracellular Signal

Mechanical stimuli are important signals in articular cartilage, but what mediates them is unknown. We have shown that extracellular-signal-regulated kinase was activated on cutting and loading articular cartilage, and deduced that this was due to the release of bFGF (basic fibroblast growth factor) from the tissue. bFGF was shown to be extracellular, and by immunohistochemistry, was present in the pericellular matrix of articular chondrocytes attached to the heparan sulphate proteoglycan perlecan. We propose a novel mechanotransduction model, whereby pericellular bFGF, a short distance from the cell surface, becomes available to the cell surface tyrosine kinase receptors when articular cartilage is loaded.

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Basic fibroblast growth factor-syndecan complex at cell surface or immobilized to matrix promotes cell growth.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)37085-1 ◽

1992 ◽

Vol 267 (25) ◽

pp. 17606-17610 ◽

Cited By ~ 1

Author(s):

M Salmivirta ◽

J Heino ◽

M Jalkanen

Keyword(s):

Growth Factor ◽

Cell Growth ◽

Cell Surface ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Fibroblast Growth

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Evaluation of the bioactivity about anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold for pelvic reconstruction

Journal of Biomaterials Applications ◽

10.1177/0885328218811390 ◽

2018 ◽

Vol 33 (6) ◽

pp. 808-818 ◽

Cited By ~ 2

Author(s):

Jiankui Li ◽

Xi Chen ◽

Kaijian Ling ◽

Zhiqing Liang ◽

Huicheng Xu

Keyword(s):

Growth Factor ◽

Urinary Bladder ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Pelvic Organ ◽

Fibroblast Growth ◽

Pelvic Reconstruction ◽

Urinary Bladder Matrix

Introduction and hypothesis: Pelvic support structure injury is the major cause of pelvic organ prolapse. At present, polypropylene-based filler material has been suggested as a common method to treat pelvic organ prolapse. However, it cannot functionally rehabilitate the pelvic support structure. In addition to its poor long-term efficiency, the urinary bladder matrix was the most suitable biological scaffold material for pelvic floor repair. Here, we hypothesize that anti-sca-1 monoclonal antibody and basic fibroblast growth factor were cross-linked to urinary bladder matrix to construct a two-factor bioscaffold for pelvic reconstruction. Methods Through a bispecific cross-linking reagent, sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (sulfo-smcc) immobilized anti-sca-1 and basic fibroblast growth factor to urinary bladder matrix. Then scanning electron microscope and plate reader were used to detect whether the anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold was built successfully. After that, the capacity of enriching sca-1 positive cells was measured both in vitro and in vivo. In addition, we evaluated the differentiation capacity and biocompatibility of the scaffold. Finally, western blotting was used to detect the level of fibulin-5 protein. Results The scanning electron microscope and plate reader revealed that the double-factor biological scaffold was built successfully. The scaffold could significantly enrich a large number of sca-1 positive cells both in vitro and in vivo, and obviously accelerate cells and differentiate functional tissue with good biocompatibility. Moreover, the western blotting showed that the scaffold could improve the expression of fibulin-5 protein. Conclusion The anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold revealed good biological properties and might serve as an ideal scaffold for pelvic reconstruction.

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