Matrix-dependent perturbation of TGFβ signaling and disease

Abstract

Transforming growth factor beta (TGFβ) is a multipotent cytokine that is sequestered in the extracellular matrix (ECM) through interactions with a number of ECM proteins. The ECM serves to concentrate latent TGFβ at sites of intended function, to influence the bioavailability and/or function of TGFβ activators, and perhaps to regulate the intrinsic performance of cell surface effectors of TGFβ signal propagation. The downstream consequences of TGFβ signaling cascades in turn provide feedback modulation of the ECM. This review covers recent examples of how genetic mutations in constituents of the ECM or TGFβ signaling cascade result in altered ECM homeostasis, cellular performance and ultimately disease, with an emphasis on emerging therapeutic strategies that seek to capitalize on this refined mechanistic understanding.

Figure 1

Integrated signaling cascades in Marfan syndrome and related diseases. Canonical (green) and noncanonical (blue) TGFβ signaling cascades, as well as intracellular proteins not currently implicated in downstream TGFβ signaling (red), are illustrated according. Disorders caused by a mutated gene product are shown in brackets next to the protein. Drugs shown in green have been tested in Marfan mice and/or patients. Drugs shown in red are untested but may have hypothetical benefit, based on our current understanding of disease pathogenesis. MFS: Marfan syndrome; SSS: Stiff skin syndrome; WMS: Weill-Marchesani syndrome; ELS: Ectopia lentis syndrome; GD: Geophysic dysplasia; AC: Acromelic dysplasia; HHT T1: Hereditary hemorrhagic telangiectasia Type 1; HHT T2: Hereditary hemorrhagic telangiectasia Type 2; ATS: Arterial tortuosity syndrome; PVNH: Periventricular nodular heterotopia; LDS: Loeys Dietz syndrome; iFTAA: Isolated familial thoracic aortic aneurysm; FSS: Ferguson Smith syndrome. NAb: neutralizing antibody; ARB: Angiotensin II Type 1 receptor blocker (e.g. losartan); ACEi: Angiotensin-converting enzyme inhibitor (e.g. enalapril).

Figure 2

Extracellular matrix proteins influencing TGFβ and other pathways in disease. Disorders caused by a mutated gene product are shown in brackets next to the protein. Cells sense stiffened matrix through integrin-mediated bridging of ECM proteins (e.g. fibrillins, fibronectin, and collagens) to the cytoskeleletal proteins such as actin and myosin. Integrins can also modulate intracellular signaling via interactions with growth factor receptors (e.g. VEGFR, PDGFR, and IGFR). Diseases: MFS: Marfan syndrome; SSS: Stiff skin syndrome; WMS: Weill-Marchesani syndrome; ELS: Ectopia lentis syndrome; GD: Geophysic dysplasia; AC: Acromelic dysplasia; CL: Cutis Laxa, EDS: Ehlers Danlos Syndrome. *Hypothetical.