TY - JOUR
T1 - A Cryptic Targeting Signal Induces Isoform-specific Localization of p46Shc to Mitochondria
AU - Ventura, Andrea
AU - Maccarana, Marco
AU - Raker, Veronica A.
AU - Pelicci, Pier Giuseppe
PY - 2004/1/16
Y1 - 2004/1/16
N2 - The human Src homology and collagen (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 66-kDa isoform has been shown to play a central role in controlling reactive oxygen species metabolism and life span 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, containing the same sequence but more internally located, display a remarkably different subcellular localization. These findings indicate that p46Shc may exert a nonredundant biological function in signal transduction pathways involving mitochondria.
AB - The human Src homology and collagen (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 66-kDa isoform has been shown to play a central role in controlling reactive oxygen species metabolism and life span 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, containing the same sequence but more internally located, display a remarkably different subcellular localization. These findings indicate that p46Shc may exert a nonredundant biological function in signal transduction pathways involving mitochondria.
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U2 - 10.1074/jbc.M307655200
DO - 10.1074/jbc.M307655200
M3 - Article
C2 - 14573619
AN - SCOPUS:0347087425
VL - 279
SP - 2299
EP - 2306
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 3
ER -