Paracrine Fibroblast Growth Factors (FGFs) are secreted proteins, and they mainly contain a cleavable N-terminal secreted signal peptide. However, the bipartite secreted signal sequences of FGF 9/16/20 are not cleaved in mature proteins. In addition, there is no N-terminal signal sequence for FGF1 and FGF2; these two FGFs are considered released from damaged cells or by an exocytotic mechanism of which the endoplasmic reticulum-Golgi pathway is not required. Paracrine FGFs bind to the tyrosine kinase FGFR receptors (FGFRs), resulting in functional dimerization, receptor transphosphorylation, and the activation of downstream signaling pathways. These FGFs contain a heparin-binding site, and the heparan sulfate on cell surface is known as a cofactor which helps their binding with receptors. Paracrine FGFs mediate the biological response of neighboring cells from a distance, and their affinities for heparin-like molecules of the extracellular matrix (ECM) regulate the range of their signaling.
Endocrine FGFs also exert their function by binding to FGFRs. However, their interaction with FGFRs and affinity for heparin/heparan sulfate are very low, which restrict them to act in an endocrine manner.
Intracrine FGFs are intracellular proteins, and they primarily work as regulators of the electrical excitability for neurons. The function of these FGFs may be induced by their interactions with intracellular domains of voltage-gated sodium channels and with the neuronal MAPK scaffold protein islet-brain-2.
Fig 3. Fibroblast Growth Factor (FGF) Structure
SP: cleavable secreted signal sequence; SP*: uncleaved bipartite secreted signal sequence; HB： heparin-binding site.
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