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Review
. 2018 Oct 18;19(10):3220.
doi: 10.3390/ijms19103220.

Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

Anna Schliermann  1 , Joachim Nickel  2   3
Affiliations
Review

Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

Anna Schliermann et al. Int J Mol Sci. .

Abstract

Ontogeny of higher organisms as well the regulation of tissue homeostasis in adult individuals requires a fine-balanced interplay of regulating factors that individually trigger the fate of particular cells to either stay undifferentiated or to differentiate towards distinct tissue specific lineages. In some cases, these factors act synergistically to promote certain cellular responses, whereas in other tissues the same factors antagonize each other. However, the molecular basis of this obvious dual signaling activity is still only poorly understood. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) are two major signal protein families that have a lot in common: They are both highly preserved between different species, involved in essential cellular functions, and their ligands vastly outnumber their receptors, making extensive signal regulation necessary. In this review we discuss where and how BMP and FGF signaling cross paths. The compiled data reflect that both factors synchronously act in many tissues, and that antagonism and synergism both exist in a context-dependent manner. Therefore, by challenging a generalization of the connection between these two pathways a new chapter in BMP FGF signaling research will be introduced.

Keywords: bone morphogenetic protein; cross-talk; fibroblast growth factor; signal integration; signal transduction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanisms of fibroblast growth factor (FGF)-bone morphogenetic protein (BMP) interactions. Depicted are canonical BMP- and FGF signal transduction pathways. BMPs are dimeric proteins, assembling heterotetrameric receptor complexes and activating R-SMAD proteins to translocate into the nucleus and influence transcription. Extracellular inhibitors like Noggin, membrane-associated inhibitors like BAMBI or intracellular inhibitors like Smurfs limit BMP signal transduction. FGFs recruit two FGF receptors and heparan sulfates into the signaling complex, and activate multiple-step cascades with effector kinases, including Erk, Akt and p38. The muscle-specific kinase MuSK is able to influence BMP signaling via binding to BMP ligands without involvement of its own kinase domain. Abbreviations: BMP—bone morphogenetic protein; Co-SMAD—common mediator SMAD; CRKL—Crk-like protein; DAG—diacylglycerol; Dusp—dual specificity phosphatase; ECM—extracellular matrix; FGF—fibroblastic growth factor; FRS2α—FGFR substrate 2α; Gab1—GRB2-associated-binding protein 1; GRB2—growth factor receptor-bound protein 2; HSPG—heparan sulfate proteoglycan; IP3—inositol triphosphate; MAPK—mitogen-activated kinase; MEK—MAPK kinase; MuSK—muscle-specific kinase; PDK1—pyruvate dehydrogenase lipoamide kinase isozyme 1; PI3K—phosphoinositide 3-kinase; PKC—protein kinase C; PIP2—phosphatidylinositol 4,5-biphosphate; PIP3—phosphatidylinositol 3,4,5-trisphosphate; PLCγ—phospholipase Cγ; PTEN—phosphatase and tensin homolog; R-SMAD—receptor-regulated SMAD; SHP2 – Src homology region 2-containing protein tyrosine phosphatase 2; Smurf—SMAD specific E3 ubiquitination regulatory factor; SOS—Son of sevenless; Spry—Sprouty; STAT—signal transducers and activators of transcription.
Figure 2
Figure 2
Examples of BMP-FGF Interaction throughout the Developing Body. BMPs and FGFs interact in (the development of) various tissues, such as the brain, lung, heart, gut, skin, eyes, teeth, kidneys, and the skeleton. Examples of a synergistic nature are flanked by a green indicator, antagonistic examples are flanked by a red indicator. (cartoon provided by www.motifolio.com).
See this image and copyright information in PMC

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