Latent TGF-β-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly

Abstract

Elastic fibers play the principal roles in providing elasticity and integrity to various types of human organs, such as the arteries, lung, and skin. However, the molecular mechanism of elastic fiber assembly that leads to deposition and crosslinking of elastin along microfibrils remains largely unknown. We have previously shown that developing arteries and neural crest EGF-like protein (DANCE) (also designated fibulin-5) is essential for elastogenesis by studying DANCE-deficient mice. Here, we report the identification of latent transforming growth factor-b-binding protein 2 (LTBP-2), an elastic fiber-associating protein whose function in elastogenesis is not clear, as a DANCEbinding protein. Elastogenesis assays using human skin fibroblasts reveal that fibrillar deposition of DANCE and elastin is largely dependent on fibrillin-1 microfibrils. However, downregulation of LTBP-2 induces fibrillin-1-independent fibrillar deposition of DANCE and elastin. Moreover, recombinant LTBP-2 promotes deposition of DANCE onto fibrillin-1 microfibrils. These results suggest a novel regulatory mechanism of elastic fiber assembly in which LTBP-2 regulates targeting of DANCE on suitable microfibrils to form elastic fibers.

Microfibril Structure Masks Fibrillin-2 in Postnatal Tissues

“…First, cell culture models for microfibril structure, which have been used previously to indicate structural differences between normal and Marfan microfibrils (25,26), may have only limited relevance to the status of microfibrils in vivo. In addition, cell culture models that are used to test mechanisms of microfibril assembly (27) may similarly have only limited relevance to in vivo mechanisms of assembly, which as we have shown result in both developmental and tissue-specific differences in microfibril structure.…”

Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation

“…Each siRNA was synthesized by Life Technologies and reverse transfected into HeLa cells using Lipofectamine RNAiMAX Reagent (Life Technologies) as previously described (60). Cells were plated at a density of 90,000 cells/well on 8-well chamber slides (Lab-Tek) after coating with Fibronectin (F1141, Sigma-Aldrich).…”

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

“…68 A truncation of LTBP2 was also identified as the causative mutation in a cat model of primary congenital glaucoma. 69 Unlike other LTBPs, LTBP2 does not bind TGFb, but it does bind fibrilllin-1 and may perform a structural role in microfibril and elastic fiber formation 70 and/or compete with other LTBPs for interaction with microfibrils. 25 A mutation in ADAMTS10 has been reported as likely causative for glaucoma in a canine model of hereditary primary open-angle glaucoma.…”