Scientists reveal how cancer cells destroy growth signal receptors
Researchers have identified the precise mechanism by which cells break down a key growth signal receptor, PDGFRβ, which could reshape how companies approach cancer drug development. The finding suggests existing cancer therapies may need redesign, since blocking this degradation pathway affects multiple signaling routes simultaneously—a critical consideration for minimizing side effects.
Originaltitel: PDGF-induced internalisation promotes proteolytic cleavage of PDGFRβ in mesenchymal cells
<p>Platelet-derived growth factor (PDGF)-induced signalling via PDGF receptor β (PDGFRβ) leads to activation of downstream signalling pathways which regulate multiple cellular responses. It is unclear how PDGFRβ is degraded; both lysosomal and proteasomal degradation have been suggested. In this study, we have characterised the proteolytic cleavage of ligand-activated PDGFRβ, which results in two fragments: a larger fragment containing the extracellular domain, the transmembrane segment, and a part of the intracellular juxtamembrane region with a molecular mass of ∼130 kDa, and an intracellular ∼70 kDa fragment released into the cytoplasm. The proteolytic processing did not take place without internalisation of PDGFRβ. In addition, chelation of intracellular Ca<sup>2+</sup> inhibited proteolytic processing. Inhibition of the proteasome affected signal transduction by increasing the phosphorylation of PDGFRβ, PLCγ, and STAT3 while reducing it on Erk1/2 and not affecting Akt. The proteolytic cleavage was observed in fibroblasts or cells that had undergone epithelial-mesenchymal transition.</p>