The Biochemical and Genetic Odyssey to the Function of a Nicastrin-Like Protein

gamma-Secretase is a high-molecular-weight protein complex required
for the proteolytic processing of various transmembrane proteins
including the Alzheimer's disease-associated amyloid precursor
protein and the signaling receptor Notch. One of the
gamma-secretase complex components is the type I transmembrane
protein nicastrin. Here we review the odyssey to a cyclopic fish,
which at the end allowed the functional analysis of nicalin, a
novel member of the nicastrin protein family. This 60-kDa protein
is part of a previously unknown membrane protein complex unrelated
to gamma-secretase and binds to Nomo (Nodal modulator, previously
known as pM5), a novel 130-kDa transmembrane protein. Both proteins
are highly conserved in metazoans and show almost identical tissue
distribution in humans. Functional studies in zebrafish embryos and
cultured human cells revealed that nicalin and Nomo collaborate to
antagonize the Nodal/TGF beta signaling pathway. Thus, nicastrin
and nicalin are both associated with protein complexes involved in
cell fate decisions during early embryonic development. Copyright
(C) 2004 S. Karger AG, Basel