The extracellular linker of pro-neuregulin-alpha2c is required for efficient sorting and juxtacrine function

The neuregulins (NRGs) play important roles in animal physiology, and their disregulation has been linked to diseases such as cancer or schizophrenia. The NRGs may be produced as transmembrane proteins (proNRGs), even though they lack an N-terminal signal sequence. This raises the question of how NRGs are sorted to the plasma membrane. It is also unclear whether in their transmembrane state, the NRGs are biologically active. During studies aimed at solving these questions, we found that deletion of the extracellular juxtamembrane region termed the linker, decreased cell surface exposure of the mutant proNRG ΔLinker, and caused its entrapment at the cis-Golgi. We also found that cell surface-exposed transmembrane NRG forms retain biological activity. Thus, a mutant whose cleavage is impaired but is correctly sorted to the plasma membrane activated ErbB receptors in trans and also stimulated proliferation. Because the linker is implicated in surface sorting and the regulation of the cleavage of transmembrane NRGs, our data indicate that this region exerts multiple important roles in the physiology of NRGs. © 2007 by The American Society for Cell Biology.
This work was supported by a grant from the Ministry of Science and Technology of Spain (BMC2003-01192). R.R.-B. and L.Y. were supported by fellowships from the Ministry of Education and Culture, and A.E.O. was initially supported by the Scientific Foundation of the Spanish Association for Cancer Research (AECC), and later by the Instituto de Salud Carlos III. J.B. was supported by a Fundaçcâo para a Ciência e a Tecnologia (FCT/FSEIII), Quadro Comunitario de Apoio III.