SHC1 Human

SHC-Transforming Protein 1, also known as SHC1, is a protein encoded by the SHC1 gene in humans. This protein plays a crucial role in cellular signaling pathways, particularly those involved in cell growth, differentiation, and apoptosis. SHC1 is a member of the SHC (Src Homology 2 domain-containing) family of adaptor proteins, which are essential for transmitting signals from activated cell surface receptors to intracellular signaling pathways .

The SHC1 gene is located on chromosome 1 and encodes three main protein isoforms: p66SHC, p52SHC, and p46SHC. These isoforms differ in their molecular weights and subcellular locations. The p66SHC isoform is the longest and contains an additional N-terminal CH2 domain, while p52SHC and p46SHC link activated receptor tyrosine kinases to the RAS pathway .

All three SHC1 proteins share a common domain arrangement, consisting of an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal Src-homology2 (SH2) domain. These domains enable the proteins to bind to tyrosine-phosphorylated proteins, although they exhibit different phosphopeptide-binding specificities .

SHC1 proteins function as signaling adapters that couple activated growth factor receptors to downstream signaling pathways. Isoforms p46SHC and p52SHC, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex, thereby initiating the Ras signaling cascade in various non-neuronal systems. In contrast, the p66SHC isoform does not mediate Ras activation but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and lifespan .

Overexpression of SHC1 proteins has been associated with cancer mitogenesis, carcinogenesis, and metastasis. The SHC1 proteins transmit signals from cell surface receptors such as the epidermal growth factor receptor (EGFR), erbB-2, and insulin receptors. The p52SHC and p46SHC isoforms activate the Ras-ERK pathway, while p66SHC inhibits ERK1/2 activity and promotes stress-induced apoptosis .

The p66SHC isoform is particularly significant in regulating oxidative stress and apoptosis. It acts as a downstream target of the tumor suppressor p53 and is essential for the ability of stress-activated p53 to induce the elevation of intracellular oxidants, cytochrome c release, and apoptosis. The expression of p66SHC has been correlated with lifespan and is involved in mediating steroid action through the redox signaling pathway .

Given its role in cellular signaling and apoptosis, SHC1 is of great interest in cancer research. Overexpression of SHC1 proteins has been linked to various cancers, including breast cancer and multiple endocrine neoplasia. Understanding the function and regulation of SHC1 proteins could provide valuable insights into cancer development and potential therapeutic targets .