April 2021

SH3BP4 -- the link between adhesion and Akt signaling 

In a paper published in the April issue of Developmental Cell, Christoph Burckhardt describes his discovery of the mechanism by which SH3BP4 mediated in an Akt-dependent fashion endocytosis of α5-integrin and neuroplin-1. PI3K/Akt signaling is one of the most frequently activated pathways in cancer and critical for the regulation of cell metabolism. However, it is less clear how Akt regulates mechanotransduction. By combining quantitative microscopy and biochemical assays, Christoph found that phosphorylated SH3BP4 in complex with 14-3-3 adaptors is excluded from clathrin coated pits (CCPs). Conversely, in the absence of Akt phosphorylation, SH3BP4 accumulates at CCPs and binds adaptor proteins such as Eps15 and GIPC1. Together, this protein complex promotes the endocytic uptake of α5-integrin and neuroplin-1. Thus, in the presence of active SH3BP4, the surface expression of α5-integrin is reduced. In a collaboration with Dr. John Minna, he then found that in chemorepellent semaphorin-3a outside-in signaling, SH3BP4 was activated and promoted integrin and neuropilin endocytosis and cell contraction. Finally, lung cancer cells with high Akt activities developed resistance to semaphorin-3a by excluding SH3BP4 from CCPs. Based in these data Christoph proposes a model, in which SH3BP4 modulates cell matrix interactions in response to internal and external cues via endocytosis of neuropilin-1 and α5-integrin receptors. This places SH3BP4 at the intersection of signaling and membrane trafficking.