Integrin-mediated Latency-Associated Peptide (LAP) activation complex (Integrin-LAP complex)

The Integrin-mediated Latency-Associated Peptide (LAP) activation complex is a critical regulatory hub for the bioavailability of Transforming Growth Factor-beta (TGF-beta). TGF-beta is synthesized as a pro-protein and secreted as a latent complex where the mature growth factor is non-covalently sequestered by the LAP domain [1: PubMed 28232556]. This complex is often anchored to the extracellular matrix via Latent TGF-beta Binding Proteins (LTBPs) or to the cell surface via GARP (LRRC32) [2: PubMed 30635515]. Specific integrins, particularly alpha-v-beta-6 (avb6) and alpha-v-beta-8 (avb8), recognize the RGD motif within the LAP domain to trigger the release of active TGF-beta [3: PubMed 31533831]. In pathological states like idiopathic pulmonary fibrosis, overexpressed integrins facilitate excessive TGF-beta activation, leading to myofibroblast differentiation and collagen deposition [4: PubMed 33033131]. In the tumor microenvironment, this activation mechanism contributes to immune exclusion and suppression of cytotoxic T-cell responses [5: PubMed 32439602]. Therapeutic agents targeting this complex, such as selective integrin inhibitors or LAP-stabilizing antibodies, aim to block TGF-beta activity locally at the site of disease [6: PubMed 29138237]. This approach is designed to avoid the severe systemic toxicities, such as cardiovascular issues and autoimmunity, associated with global TGF-beta signaling inhibition [7: PubMed 24610813]. Current clinical candidates include small molecules like bexotegrast and monoclonal antibodies like SRK-181, which are being evaluated for fibrosis and oncology indications respectively [8: ClinicalTrials.gov NCT04670679].

Other names

TGF-beta activation complexLAP-integrin axisAlpha-v integrin-LAP complexLatent TGF-beta binding partnersGARP-TGF-beta complexLTBP-TGF-beta complex

Inhibition of the mechanical or proteolytic release of active TGF-beta from its latent form by blocking the interaction between integrins and the Latency-Associated Peptide (LAP) or by stabilizing the LAP-TGF-beta complex.