A Cbl:clathrin complex involved in NGF signaling for neurite outgrowth

AbstractCbl regulates receptor tyrosine kinase activity by promoting the endocytosis of receptors from the plasma membrane. The mechanism of this effect is unclear, but recent evidence suggests that Cbl mediates ubiquitin‐dependent sorting of receptors following recruitment to phosphotyrosine motifs in the activated receptor. Moreover, recent findings support a role for Cbl in the clathrin‐mediated endocytosis of receptor tyrosine kinases. We provide evidence that Cbl is found in complex with clathrin and is localized to clathrin‐coated vesicles following NGF stimulation of TrkA. We also show that overexpression of Cbl enhances clathrin‐mediated endocytosis of 125I‐NFG, and that this increased internalization is correlated with a substantial acceleration of neurite outgrowth in response to NGF. Our data suggest that Cbl may participate in the formation of a multi‐protein complex involved in the clathrin‐mediated endocytosis of receptor tyrosine kinases, and that Cbl may function as a positive regulator of such kinases in specific cellular contexts.