THE activated insulin receptor phosphorylates various cellular substrates on tyrosine residues [1]. These substrates include the insulin receptor substrate family (IRS-1,-2,-3,-4). IRS functions as a multisite docking protein that interacts with the src homology 2 (SH2) domains of various signal-transducing molecules, including p85 subunit of PI3-kinase, Grb2, SHP2, Nck, and Fyn to propagate the insulin signal downstream [1]. Among them, PI3-kinase is a key molecule to mediate many of insulininduced metabolic signaling [1]. Shc is another substrate of the insulin receptor [1, 2]. It is so named because Shc contains a SH2 domain and a Collagenhomologous region, and is composed of an aminoterminal phosphotyrosine binding (PTB) domain, a central collagen homology (CH) domain, and a carboxyl-terminal SH2 domain (Fig. 1)[3]. Anti-Shc antibody recognizes three distinct 46-, 52-, and 66-kDa isoforms of Shc [3]. All of these Shc isoforms originate from alternative splicing of a primary Shc transcript [3, 4]. The 46-and 52-kDa proteins are ubiquitously expressed except in the central nervous system, while the 66-kDa Shc protein is absent in some hematopoietic cells [3, 4]. These three classical Shc isoforms are also referred to collectively as ShcA [5, 6]. Two ShcA related genes, ShcB/Sck and