Hieda et al. In its nuclear envelope locale, the protein can reactivate cell cycle genes.
Activation of the cell cycle is an important job for EGF family members. These transmembrane proteins start out on the plasma membrane but are cleaved when cells receive mitogenic cues, thereby generating a soluble extracellular growth factor. Although the cytoplasmic portion remains hitched to the transmembrane domain, recent evidence indicates that this portion of one EGF member, HB-EGF, inactivates transcriptional repressors of cell cycle genes.
The new work suggests that this transcriptional function requires HB-EGF relocation from the plasma membrane to the INM. Upon cleavage, trafficking of the remaining protein to the INM depended on Rab GTPases that are required in the endocytic pathway. It also depended on an ER retrieval signal within the HB-EGF. The protein thus seems to be recycled in endosomes to the Golgi, where the ER retrieval signal operates. Once at the ER, the protein is small enough to diffuse freely within the membrane through the nuclear pore to the INM.
In the absence of mitogenic cues, the ER retrieval signal must be stymied for HB-EGF to pass from the Golgi to the plasma membrane. The authors imagine that the signal—a 5-aa sequence—is structurally hidden within HB-EGF but exposed by a mitogen-activated phosphorylation event.
Hooked to the INM, HB-EGF is probably in close proximity to its repressor targets, since sites of gene repression are thought to reside near the nuclear envelope. The group is now examining whether genes that are repressed by HB-EGF's targets lie near the envelope.