LTBPs

LTBPs, or latent transforming growth factor beta binding proteins, are a small family of large extracellular matrix glycoproteins that regulate transforming growth factor beta (TGF-β) signaling. In humans there are four members: LTBP-1, LTBP-2, LTBP-3, and LTBP-4. They are secreted proteins related to the fibrillin family and are integrated into extracellular microfibrils. The family was identified in part by sequence similarity to fibrillins and their role in binding latent TGF-β complexes.

LTBPs feature multiple calcium-binding EGF-like repeats and TB domains that mediate high affinity binding to latent TGF-β (the latent complex composed of TGF-β bound to latency-associated peptide). They also interact with other matrix components, assisting in the storage of latent TGF-β within the ECM and guiding deposition onto microfibrils.

The primary function of LTBPs is to sequestrate latent TGF-β in the extracellular matrix and regulate its activation. Mechanical forces transmitted through the ECM or cellular receptors can release and activate TGF-β from the complex, enabling signaling in surrounding cells. LTBPs also contribute to extracellular matrix assembly and elastogenesis, with particular roles in microfibril structure and tissue integrity.

There are notable differences among family members. LTBP-1 and LTBP-3 are closely associated with latent TGF-β complexes and modulate signaling, while LTBP-2 does not bind TGF-β with the same affinity and is more involved in microfibril assembly in some tissues. LTBP-4 has roles in elastin-related matrix organization and may participate in TGF-β regulation in specific contexts; alternative splicing generates isoforms with varied functions.

Mutations and dysregulation of LTBP genes have been linked to human disease. LTBP2 mutations cause primary congenital glaucoma and ocular connective tissue defects; LTBP4 mutations are associated with autosomal recessive cutis laxa and elastin anomalies. Ongoing research continues to clarify the diverse roles of LTBPs in development, tissue homeostasis, and fibrosis.