Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling.

Previous work demonstrated an essential role for the atypical protein kinase C interacting protein, p62, in neurotrophin survival and differentiation signaling. Here we show that p62 interacts not only with TrkA but also with TrkB and TrkC, which are the primary receptors for brain-derived neurotrophic factor and neurotrophin-3. The interaction of p62 with TrkA requires the kinase activity of TrkA. Mapping analysis indicates that p62 does not compete with Shc for binding to TrkA, and p62 association was confined to the juxtamembrane region of TrkA, amino acids 472-493. By immunofluorescence the colocalization of p62 and TrkA was observed 30 min post-nerve growth factor treatment within overlapping vesicular structures. Upon subcellular fractionation, activated TrkA colocalized to an endosomal compartment and p62 was coassociated with the receptor post-nerve growth factor stimulation. Moreover, an absence of p62 blocked internalization of TrkA without an effect on phosphorylation of either TrkA or MAPK; however, Erk5 signaling was selectively abrogated. We propose that p62 plays a novel role in connecting receptor signals with the endosomal signaling network required for mediating TrkA-induced differentiation.