Regulation of Fibroblast Activation Protein-α Expression: Focus on Intracellular Protein Interactions

Abstract

The prolyl-specific peptidase fibroblast activation protein-α (FAP-α) is expressed at very low or undetectable levels in nondiseased human tissues but is selectively induced in activated (myo)fibroblasts at sites of tissue remodeling in fibrogenic processes. In normal regenerative processes involving transient fibrosis FAP-α + (myo)fibroblasts disappear from injured tissues, replaced by cells with a normal FAP-α − phenotype. In chronic uncontrolled pathological fibrosis FAPα + (myo)fibroblasts permanently replace normal tissues. The mechanisms of regulation and elimination of FAP-α expression in(myo)fibroblasts are unknown. According to a yeast two-hybrid screen and protein databanks search, we propose that the intracellular (co)-chaperone BAG6/BAT3 can interact with FAP-α, mediated by the BAG6/BAT3 Pro-rich domain, inducing proteosomal degradation of FAP-α protein under tissue homeostasis. In this Perspective, we discuss our findings in the context of current knowledge on the regulation of FAP-α expression and comment potential therapeutic strategies for uncontrolled fibrosis, including small molecule degraders (PROTACs)-modified FAP-α targeted inhibitors.

Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein

“…Cancer-associated fibroblasts (CAFs) are central components of the tumor microenvironment (TME) and play crucial roles in tumor development, immune suppression, and cancer invasion. − A notable biomarker highly expressed in CAFs is the fibroblast activation protein (FAP), a type II membrane-bound glycoprotein. FAP is upregulated in numerous epithelial carcinomas, wound healing, arthritis, atherosclerotic plaques, and fibrosis, with little expression in normal tissues. − Thus, it is considered a promising target for cancer diagnosis and therapy. − …”

Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance

“…However, normal tissues and healthy activated fibroblasts also express FAP during wound healing, such as the activation of myofibroblasts post-myocardial infarction. While both LRRC15 and FAP have been shown to be upregulated by TGFβ (30), recent studies revealed a unique subset of TGFβ-driven CAFs that express LRRC15 and are negative for FAP expression (4, 8), and that these LRRC15+ CAFs are associated with CD8+ T-cell exclusion (8). During our therapeutic studies, a notable observation emerged: LRRC15+ tumors exhibited a concurrent reduction in both growth and the TGFβ–LRRC15 gene signature upon exposure to RIT.…”

Fibroblast Activation Protein Alpha (FAPα) in Fibrosis: Beyond a Perspective Marker for Activated Stromal Cells?

“…Negative regulators of FAPα expression include estrogens and activators of PTEN protein [86,87]. Importantly, the FAPα promoter region is known to contain binding sites for several transcription factors-AREB6, ITF-2, Meis-1, PPAR-gamma1, PPAR-gamma2, and Tal-1beta [88].…”