The human Src homology and
collagene (Shc) gene encodes three protein isoforms of 46, 52 and 66 kDa,
that belong to a family of molecular adapters involved in several signal
transduction pathways. Recently, the 66kDa isoform has been shown to play
a central role in controlling reactive oxygen species (ROS) metabolism and
lifespan in mammals. Despite the large amount of information available on
the biology and biochemistry of Shc proteins, very little is known
regarding the regulation of their subcellular localization. Here we
demonstrate the specific and selective localization of p46Shc to the
mitochondrial matrix. Through deletion mapping experiments, we show that
targeting of p46Shc to mitochondria is mediated by its first 32 amino
acids, which behave as a bona fide mitochondrial targeting sequence. We
further demonstrate that the N-terminal location of the signal peptide is
critical for its function. This accounts for the observation that p52Shc
and p66Shc, that contain the same sequence but more internally located,
display a remarkably different subcellular localization. These findings
indicate that p46Shc may exert a non-redundant biological function in
signal transduction pathways involving mitochondria
