SHC1 gene covers 12,066 bp of DNA on q21.3 arm of chr1 and counts 13 exons and 13 introns.

SHC1 locus produces two distinct transcripts directed from alternative promoters; altogether they encode for three overlapping protein isoforms of 66, 52, and 46 kDa thus called p66Shc, p52Shc and p46Shc. The first transcript (NM_003029) is 3,076 bp long and specifically encodes for the p52 and p46 forms from two different in-frame ATGs and derives from the splicing of the first non-coding exon to an internal site of the second exon; this process produces the skipping of the sequence that encodes for the longest p66Shc isoform. The second transcript (NM_183001 and BX647149) is 3,497bp long, it is transcribed starting from the beginning of the second exon, under the regulation of a different promoter and it encodes for all three p66, p52 and p46Shc isoforms by means of alternative ATGs usage.

Two possible processed pseudogenes of SHC1 are located on chrX and chr17.

Regardless of their high structural similarity, a growing bunch of experimental evidences suggests that the p66Shc and p52/p46Shc isoforms are functionally non-redundant. P66, p52 and p46Shc consist of 583, 474 and 428 aa, respectively. All the three SHC1 protein isoforms share the same basic modular organization: they contain two different phosphotyrosine-binding domains, namely a PTB domain in the amino-terminal and a SH2 in the carboxy-terminal, separated by a poorly characterized glycine/proline-rich region rather similar to the collagen protein and therefore called Collagen Homology domain 1, CH1. In vitro experiments suggest that the "proline rich motif" found in the CH1 domain might be responsible for the interaction between p52Shc and the SH3 domain of SRC, LYN, FYN cytoplasmic tyrosine kinases, but the functional role of this interaction is still unclear and there are no genetic or biochemical evidences that these proteins interact in vivo. The longest p66Shc isoform contains a supplementary amino-terminal glycine/proline-rich region, called CH2. The N-term PTB and C-term SH2 modularity is an exclusive feature of the Shc protein family. Both PTB and SH2 domains bind to phosphorylated tyrosines within specific, short peptide sequences: amino-terminal residues immediately adjacent to the pY confer specificity on PTB domain; conversely carboxy-terminal amino acids draw specificity for the SH2. The CH1 region contains three key tyrosines, Y239, Y240 and Y317 that become phosphorylated upon commitment of a number of cell surface ligand-activated receptors. Recently, in murine systems, was demonstrated that SHC1 may signal through the CH1 pYs motif both in a dependent and independent manner supporting different pathways in tissue morphogenesis. The p66Shc specific CH2 region does not become tyrosine phosphorylated, but gets phosphorylation on serine 36 (S36) upon oxidative stress; Tetradecanoylphorbol-13-acetate (TPA) induces phosphorylation both of Ser 36 and Ser 138 of p66Shc. A new functional region, the "redox centre", responsible for cytochrome c binding, has been recently characterized within the p66Shc CH2-PTB domains. It has been mapped within a portion that presents the highest degree of identity in sequence alignments of p66Shc vertebrate orthologous and it is essential for the p66Shc function in ROS regulation. This region (designated CB, for cytochrome c binding) contains three glutamic acid (E125, E132, E133) and two tryptophan (W134 and W148) conserved residues.

p52/p46Shc are widely expressed in cultured cell and in almost all adult mouse tissues with an invariable relative amount; p66Shc protein instead shows a more peculiar pattern since it is expressed in the most of cells except in the hematopoietic lineage, where it is absent or barely recognizable. During early rat embryonic development SHC1 is most significantly expressed in the endothelium, in mesenchymal cells of the cardiovascular system and in the forebrains area of active proliferation of immature neuroblasts. In postnatal and adult rat brain, SHC1 mRNAs and proteins are not expressed. In the adult olfactory epithelium, in which neuronal cell renewal occurs throughout life, SHC1 remained strongly expressed. In both human and murine adult tissues, p52Shc and p46Shc (mRNA and proteins) are ubiquitously expressed, while p66Shc is expressed at different levels in specific tissues, such as lung, spleen, liver, heart, and kidney and is absent in the hematopoietic lineage.
The level of p66Shc mRNA is highest in human dermal fibroblasts (DFs) from centenarians in respect to DFs from old and young people suggesting that the expression of p66Shc increases with age and associates with human longevity.

P52Shc proteins is localized on endoplasmic reticulum membranes and is redistributed after tyrosine kinase receptor activation; p46Shc localizes to the mitochondrial matrix via a N-terminal mitochondrial targeting signal. The p66Shc isoform localizes in different intracellular compartments including endoplasmic reticulum and mitochondria.

P52/p46Shc and the p66Shc proteins carry out very different cellular roles, therefore p52/p46Shc and p66Shc functions are individually described.

P52/p46Shc

• Ras regulation. Upon growth factor stimulation p56Shc physically associate with the activated receptor tyrosine kinases via the SH2 domain and become rapidly and efficiently tyrosine-phosphorylated in three major tyrosine residues present in the CH1 domain (Y239/240, Y317). Tyrosine phosphorylation mediates interactions with the SH2 domain of the Grb2 adaptor protein that is constitutively complexed with Sos, an ubiquitously expressed Ras guanine nucleotide exchange factor. Recruitment of the Grb2/Sos complex by phosphorylated p52/p46Shc proteins results in the membrane relocalization of Sos, an event considered sufficient to induce Ras activation.
  
• Growth factors signaling and survival. P52/p46Shc has been shown to function in signaling of many receptors that are themselves tyrosine kinases, such those for epidermal growth factor (EGF), Insulin (I), platelet growth factor (PDGF), nerve growth factor (NGF), hepatocyte growth factor/scatter factor (HGF/SF and ErbB2, but it also signals on receptors associated with cytoplasmic tyrosine kinases such as the antigen T and B cell receptors, and those for the Stem cell factor (SCF) otherwise known as KIT ligand or Steel factor (SLF), granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO) and interleukin IL-2, IL-3, IL-5. In particular, in the interleukin receptors signaling, SHC1, binding to the Grb2-Gab2 complex, also has an essential role in the PI-3K/Akt pathway. It was reported that Shc could regulate c-Myc activation in response to IL-3 stimulation but little is known about mechanism and target genes affected.
  
• Signaling by cell adhesion molecules. The role of SHC1 in signaling lastly includes the integrin family and G-protein coupled receptors. Indeed, in endothelial cells, beside the roles in mediating Receptor Tyrosine Kinases signaling, Shc was recently demonstrated contributing to sense shear stress, which is the mechanical force generated by the blood fluid moving along the vascular endothelium. SHC1 exerts a role in all mechanisms described to be responsible for the mechano-transduction signaling that are TRK pathways, cell matrix adhesion through integrins binding and cell-cell adhesion by interaction with cadherins in adherent junctions.
  
• Cytoskeleton Organization. MEFs lacking p52/p46Shc exhibit defective cytoskeletal organization and reduced ERK activation when plated on fibronectin (an extracellular matrix protein), a defect that is rescued reintroducing p52/p46Shc.
  
• Animal model. SHC1 knock-out is embryonic lethal, infact SHC1 mutants die by E11.5 with evidence of a gross cardiovascular defect.

P66Shc

• Negative regulation of growth factors signaling. In contrast to p52Shc, overexpression of p66Shc is incapable of transforming mouse fibroblasts, does not induce MAPK activation and has a negative effect on the FOS promoter in an a transactivation assay.
  
• ROS production. P66Shc is involved in the intracellular pathway(s) that regulates reactive oxygen species (ROS) metabolism and apoptosis. For this function, p66Shc uses reducing equivalents of the mitochondrial electron-transfer chain through the direct oxidation of cytochrome c forming hydrogen peroxide that in turn induces mitochondrial permeability pore opening and apoptosis.
  
• Animal model. P66Shc is a genetic determinant of life span in mammals, as its deletion in mice (p66Shc-/-) results in retarded aging, decreased incidence of aging-associated diseases, such as atherosclerosis, and prolonged life span. p66Shc-generated ROS is implicated in regulation of insulin signaling in the fat tissue, suggesting that intracellular oxidative stress might accelerate aging by favoring fat deposition and increasing the incidence and penetrance of fat-related disorders.

P52Shc protein is highly conserved during evolution accounting homologues already in worms and insects; the longest isoform, p66Shc seems to represent a later specialization of the protein being arisen later in the evolution, infact the first organisms where it can be found are fishes.

The SHC1 genes polymorphisms known in the coding region correspond to Met225Val in the p46 isoform, Met300Val in the p52 isoform and to Met410Val in the p66 isoform. This polymorphism has been associated with a significantly decreased risk for breast cancer, strongly in women diagnosed below the age of 50. The same polymorphism in SHC1 was associated with longevity.