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(DeltaLinker), 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.
Montero
Juan C
JC
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, 37007 Salamanca, Spain.
Rodríguez-Barrueco
Ruth
R
Yuste
Laura
L
Juanes
Pedro P
PP
Borges
Joana
J
Esparís-Ogando
Azucena
A
Pandiella
Atanasio
A
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D020890:Neuregulin-1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics; D021381:Protein Transport; D051381:Rats; D017384:Sequence Deletion
D066246:ErbB Receptors; D020890:Neuregulin-1; D021382:Protein Sorting Signals; C490580:Nrg1 protein, rat