Extracellular microfibrils: contextual platforms for TGFbeta and BMP signaling

Abstract

The extracellular matrix plays a key role in organ formation and tissue homeostasis. Recent studies have revealed that fibrillin assemblies (microfibrils) confer both tissue integrity and regulate signaling events that instruct cell performance and that perturbation of either function manifests in disease. These analyses have also indicated that fibrillin assemblies impart contextual specificity to TGFbeta and BMP signaling. Moreover, correlative evidence suggests functional coupling between cell-directed assembly of microfibrils and targeting of TGFbeta and BMP complexes to fibrillins. Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals with TGFbetas and BMPs as nodal points that convert extracellular inputs into discrete and context-dependent cellular responses.

Figure 1

Schematic representation of the fibronectin-directed, HSPG-dependent processes of microfibril assembly (A) and LTBP and LLC incorporation into the ECM (B). Relevant steps discussed in the text include (1) promotion of fibronectin fibrillogenesis by the cytoskeleton/integrin complex; (2) fibronectin and HSPG supporting C-terminal association of fibrillin monomers into bead-like structures (grey circle with dotted outline), and (3) their subsequent linear assembly into microfibrils; (4) HSPG-dependent incorporation of LTBPs and LLCs onto fibronectin fibrils, and (5) their subsequent transfer to nascent microfibrils through ill-defined cellular activities. Also shown are (6) microfibrils decorated by LTBPs and LLC in the overlaps (beads in (8)) between the N- and C-terminal ends of fibrillins, and (8) a schematic rendition of the beads-on-a-string microfibril structure with LLCs bound to the beads [5].

Figure 2

Model of normal regulation of TGFβ by microfibrils (WT) and perturbations associated with microfibril deficiency in Marfan syndrome (MFS). Two models of MFS pathogenesis leading to loss of tissue integrity (bottom) are shown. In the first model (a), physiological levels of activators (proteases (blue indented ovals) and integrins (grey symbols)) drive disease by increasing release of TGFβ (red diamonds) from matrix-free LLCs (blue rectangle with red diamond). In the second model (b), cells enhance TGFβ activity by producing more proteases, by increasing integrin-mediated LLC activation (also through heightened cytoskeletal tension (black lines)), and by stimulating stress-response signaling pathways (yellow stars). Although the two models focus on the onset of MFS pathogenesis, impaired LLC sequestration (model (a)) could be the immediate trigger of cellular responses to an abnormal matrix (model (b)).