Multiple endogenous growth factor receptors (indirect activation via released ligands) (RTK transactivation)

This target entry refers to the indirect activation of multiple endogenous growth factor receptors, a process frequently termed receptor tyrosine kinase (RTK) transactivation. In this mechanism, an external stimulus—often the activation of a G protein-coupled receptor (GPCR)—triggers intracellular signaling pathways that activate membrane-bound metalloproteinases, such as ADAM (A Disintegrin and Metalloproteinase) family members (Higashiyama et al., 2008, Cancer Science). These enzymes then cleave and release membrane-anchored pro-ligands, such as pro-epidermal growth factor (pro-EGF) or transforming growth factor-alpha (TGF-alpha). The released mature ligands subsequently bind to and activate their respective growth factor receptors, leading to downstream signaling cascades like the MAPK/ERK or PI3K/Akt pathways (Ohtsu et al., 2006, Arteriosclerosis, Thrombosis, and Vascular Biology). This indirect activation plays a critical role in physiological processes such as cell proliferation and wound healing, but it is also a major driver in pathological states including cancer progression, cardiac hypertrophy, and vascular remodeling. Therapeutic strategies targeting this process include the use of RTK inhibitors, monoclonal antibodies against ligands, or metalloproteinase inhibitors to prevent ligand shedding (IUPHAR/BPS Guide to Pharmacology).

Other names

Receptor tyrosine kinase transactivationGPCR-mediated RTK activationTriple membrane passing signal (TMPS) mechanismIndirect growth factor receptor activationMetalloproteinase-dependent ligand shedding

Indirect activation occurs when an initial stimulus (typically G protein-coupled receptor activation) triggers the proteolytic cleavage of membrane-anchored pro-ligands by metalloproteinases (e.g., ADAM17). The liberated ligands then bind to and activate their cognate growth factor receptors (e.g., EGFR) in an autocrine or paracrine fashion (Gschwind et al., 2001, Nature Reviews Cancer; Prenzel et al., 1999, Nature).