Indirect activation of endogenous growth factor receptors

Indirect, via endogenous growth factor receptors is a pharmacological classification describing a mechanism where a drug or molecule elicits a biological response by triggering the release or activation of the body's own growth factors, rather than binding to the growth factor receptors directly. This process is most commonly exemplified by the transactivation of receptor tyrosine kinases (RTKs), such as the Epidermal Growth Factor Receptor (EGFR), following the stimulation of G protein-coupled receptors (GPCRs) by ligands like Angiotensin II or Thrombin (Daub et al., 1996, Nature). The signaling cascade typically involves the activation of intracellular kinases like Src and the subsequent recruitment of matrix metalloproteinases (MMPs) or ADAM family proteins, which shed membrane-bound pro-ligands to activate RTKs in an autocrine or paracrine fashion. This indirect pathway plays a crucial role in physiological processes such as cell proliferation, survival, and tissue repair, but it is also a major driver of pathological states including cardiac hypertrophy, vascular remodeling, and cancer progression (Gschwind et al., 2001, EMBO Journal). In the context of oncology, indirect activation is a known mechanism of resistance to targeted therapies, as cells can bypass inhibited pathways by upregulating endogenous growth factor signaling. Understanding this mechanism is vital for the development of combination therapies that can simultaneously block both direct and indirect activation of growth factor pathways to improve clinical outcomes.

Other names

Growth factor receptor transactivationIndirect growth factor signalingEndogenous growth factor inductionRTK transactivationTriple membrane passing signal

The mechanism involves the transactivation of receptor tyrosine kinases (RTKs) through a 'triple membrane passing' signal. A primary stimulus activates a G protein-coupled receptor (GPCR), which then activates a membrane-bound metalloproteinase (such as ADAM17). This enzyme cleaves a membrane-anchored growth factor precursor (like pro-HB-EGF), releasing a soluble ligand that binds to and activates its specific growth factor receptor (e.g., EGFR) (Prenzel et al., 1999, Nature). Alternatively, it may involve the transcriptional induction of growth factor genes (e.g., VEGF) by drugs like retinoids or certain vasodilators (Gille et al., 1997, Journal of Biological Chemistry).