Latent TGF-β-binding proteins

Abstract

The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, -2, -3, and -4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here. The LTBPs were first identified as forming latent complexes with TGFβ by covalently binding the TGFβ propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFβ precursor in the trans-golgi network but LAP and TGFβ remain strongly bound through non-covalent interactions. LAP, TGFβ, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFβ latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFβ activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFβ regulation, TGFβ-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly.

Keywords: Extracellular matrix; Latency associated protein; Latent TGFβ binding proteins; TGFβ activation.

Figure 1. The domain organization of the human LTBPs

Domain symbols summarized in the key to the right of the figure. Some of the alternatively spliced forms of the LTBPs in humans are illustrated (Tsuji et al. 1990; Saharinen et al. 1999) and the domain structure of human Fibrillin-1 is also shown for comparison. The letter H denotes the “hinge” region in LTBPs, the letter P denotes the proline rich region in fibrillin-1.

Figure 2. Roles of LTBP-1 in TGFβ signaling

LTBP-1 is folded and associates covalently with LAP via disulfide bonds while still inside the cell. This large latent complex (LLC) is then secreted and can associate with specific fibers in the ECM where TGFβ is held in a latent state. Latent TGFβ activation must then occur so that the growth factor can bind to it's receptors. Many different activation mechanisms have been described (Robertson and Rifkin 2013), and LTBP-1 may play a direct role in anchoring TGFβ for traction driven activation by integrins.

Figure 3. TGFβ independent roles of LTBP-2 and LTBP-4

LTBP-4 (turquoise in this figure) plays an important role in regulating elastogenesis. The hypothesized mechanism is that LTBP-4 binds fibulin-5 (orange) associated with elastin (dark red) and helps it specifically associate with the fibrillin microfibril (dark blue). It is not known whether in the ECM LTBP-4 first associates with fibrillin microfibrils or fibulin-5-elastin complexes, or both. Fibulin-5 may also bind to fibrillin independently of LTBP-4 but for simplicity this interaction is not shown (Ono et al. 2009). LTBP-2 (light green) is important for the formation and stability of microfibril bundles in mouse ciliary zonules. The precise interactions through which it performs this function are not clear but here LTBP-2 is drawn as serving a speculative bridging role for illustrative purposes.