Johan Lennartsson

Platelet-derived growth factor (PDGF)-induced signalling via PDGF receptor beta (PDGFR beta) leads to activation of downstream signalling pathways which regulate multiple cellular responses. It is unclear how PDGFR beta is degraded; both lysosomal and proteasomal degradation have been suggested. In this study, we have characterised the proteolytic cleavage of ligand-activated PDGFR beta, 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 similar to 130 kDa, and an intracellular similar to 70 kDa fragment released into the cytoplasm. The proteolytic processing did not take place without internalisation of PDGFR beta. In addition, chelation of intracellular Ca2+ inhibited proteolytic processing. Inhibition of the proteasome affected signal transduction by increasing the phosphorylation of PDGFR beta, PLC gamma, 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.

PDF file - 73K, Figure S6 The activity of PPP correlated (p<0.05) with that of vinorelbine (A), and docetaxel (B), but not with gemcitabine (C) or cisplatin (D). The correlation was 0.62 for 5-FU (not significant; data not shown).