SUMMARY
The recent discovery of metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis has expanded the functions of this classically known mitogen. To dissect the molecular basis for this functional pleiotropy, we engineered an FGF1 partial agonist carrying triple mutations (FGF1ΔHBS) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1ΔHBS exhibited a severely reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1 in vitro and in vivo. Hence, suboptimal FGFR activation by a weak FGF1-FGFR dimer is sufficient to evoke a metabolic response, whereas full FGFR activation by stable and sustained dimerization is required to elicit a mitogenic response. In addition to providing a physical basis for the diverse activities of FGF1, our findings will impact ongoing drug discoveries targeting FGF1 and related FGFs for the treatment of a variety of human diseases.
Skeletal muscle voltage-gated Na
+
channel (Na
V
1.4) activity is subject to calmodulin (CaM) mediated Ca
2+
-dependent inactivation; no such inactivation is observed in the cardiac Na
+
channel (Na
V
1.5). Taken together, the crystal structures of the Na
V
1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca
2+
-dependent CaM N-lobe binding site previously identified in Na
V
1.5 is not present in Na
V
1.4 allowing the N-lobe to signal other regions of the Na
V
1.4 channel. Consistent with this mechanism, removing this binding site in Na
V
1.5 unveils robust Ca
2+
-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca
2+
-dependent inactivation is effected by CaM’s N-lobe binding outside the Na
V
C-terminal while CaM’s C-lobe remains bound to the Na
V
C-terminal. As the N-lobe binding motif of Na
V
1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.
a b s t r a c tDuring the last three decades, a number of B-lymphocyte specific surface antigens have been defined some of which may also show activation/differentiation specific expression. Here, we review the various signaling events and the receptor-ligand interactions for B-cell development, activation and differentiation. Our discussion and presentation include reviewing the in vivo and in vitro mechanisms. Focus is on the experiments that give us valuable insights into the B cell signaling mechanisms in vitro. Three significant pathways in B-cell development -c-Kit, FLT-3 and IL-7 signaling pathways are elucidated upon. Both antigen dependent and antigen independent mechanisms of B cell stimulation are also reviewed.
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