Specificity of latent TGF‐β binding protein (LTBP) incorporation into matrix: Role of fibrillins and fibronectin

Abstract

Fibrillin microfibrils are extracellular matrix structures with essential functions in the development and the organization of tissues including blood vessels, bone, limbs and the eye. Fibrillin-1 and fibrillin-2 form the core of fibrillin microfibrils, to which multiple proteins associate to form a highly organized structure. Defining the components of this structure and their interactions is crucial to understand the pathobiology of microfibrillopathies associated with mutations in fibrillins and in microfibril-associated molecules. In this study, we have analyzed both in vitro and in vivo the role of fibrillin microfibrils in the matrix deposition of latent TGF-β binding protein 1 (LTBP-1), -3 and -4; the three LTBPs that form a complex with TGF-β. In Fbn1-/- ascending aortas and lungs, LTBP-3 and LTBP-4 are not incorporated into a matrix lacking fibrillin-1 microfibrils, whereas LTBP-1 is still deposited. In addition, in cultures of Fbn1-/- smooth muscle cells or lung fibroblasts, LTBP-3 and LTBP-4 are not incorporated into a matrix lacking fibrillin-1 microfibrils, whereas LTBP-1 is still deposited. Fibrillin-2 is not involved in the deposition of LTBP-1 in Fbn1-/- extracellular matrix as cells deficient for both fibrillin-1 and fibrillin-2 still incorporate LTBP-1 in their matrix. However, blocking the formation of the fibronectin network in Fbn1-/- cells abrogates the deposition of LTBP-1. Together, these data indicate that LTBP-3 and LTBP-4 association with the matrix depends on fibrillin-1 microfibrils, whereas LTBP-1 association depends on a fibronectin network.

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

“…The complex of TGF-β and LAP (small latent complex) also requires anchoring to the ECM through its association with Ltbp1 and Ltbp3 . For Ltbp1, this incorporation is dependent on the assembly of fibronectin, and is independent of fibrillin expression, whereas incorporation of Ltbp3 is dependent on assembly of fibrillin 1 microfibrils (Zilberberg et al, 2012). To examine whether ΔItga5/av vSMCs could incorporate Ltbp1 into the matrix, we first analysed the ability of ΔItga5/av vSMCs to assemble endogenous fibronectin into fibrils.…”

“…Interestingly, a recent study has shown that assembly of the glycoprotein fibronectin, rather than fibrillin 1, is essential for incorporation of Ltbp1 into the ECM by vSMCs (Zilberberg et al, 2012). Fibronectin is one of the first ECM proteins to be expressed around the vasculature and is essential for cardiovascular development (Astrof and Hynes, 2009).…”

Pancreatic cancer: a mechanobiology approach

“…TGF-β is secreted to the ECM in an inert/latent form complexed with much larger proteins that encapsulate TGF-β, the latency associated peptide (LAP) and latent TGF-β binding protein-1 (LTBP-1), which interface TGF-β between the fibronectin molecule in the ECM and the integrin receptors in the PSCs surface [37,38]. A spatiotemporal organisation of cellular and ECM mechanical factors including PSC contractility release TGF-β in its active form [39,40] autocrine and paracrine loop that sustains PSC activation and a tumour-favouring microenvironment.…”

Association between Fibrillin1 Polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor β1 Concentration in Human Plasma

“…According to these data, an additive minor allele model fitted best in describing the association between rs2118181 and aneurysm (odd ratio latent complex from proteolytic activation or whether FBN1 functions more directly in controlling assembly or stability of latent TGF-β1 complexes (14). Second, the balance between the need for TGF-β1 in normal development and suppression of its activity in the treatment of disease should be considered (15).…”