Platelet-derived growth factor β (PDGFRβ) is a receptor tyrosine kinase. Its activation by PDGF-BB induces cell proliferation, migration and angiogenesis. PDGFRβ is known to be internalised through clathrin-mediated endocytosis, and there is also some evidence that clathrin-independent mechanisms are engaged, although the regulators and significance of this route were unknown. Now (p. 577), Marta Miaczynska and colleagues analyse the mechanisms of PDGFRβ internalisation in human fibroblasts and identify its molecular mediators. The authors have previously shown that internalisation of PDGFRβ occurs through dynamin-dependent and -independent pathways. In this paper, they demonstrate that PDGFRβ is partly internalised by clathrin-dependent endocytosis, which is required for STAT3 activation. The authors then seek to further verify the involvement of clathrin-independent pathways in PDGFRβ internalisation, demonstrating a role for RhoA but not Rac1 in PDGFRβ uptake. They further establish that Cdc42, along with RhoA- and ROCK-mediated clathrin-independent endocytosis of PDGFRβ, are required for PDGF-induced activation of STAT3; CD44 and galectin-3 are also shown to participate. The different routes of PDGFRβ uptake cannot fully substitute for each other, suggesting that they are partly independent. Interestingly, STAT3 activation is impaired by the inhibition of any mechanism of internalisation. However, other downstream effectors of PDGFRβ, such as AKT, are not affected by the inhibition. These findings show that ligand-induced PDGFRβ internalisation can occur through multiple endocytic pathways.
