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HGNC Approved Gene Symbol: SHC1
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:154,962,298-154,974,376 (from NCBI)
The SHC gene encodes a signaling and transforming protein containing Src homology 2 and 3 (SH2 and SH3) domains. The SHC gene encodes 2 widely expressed overlapping proteins of 46 and 52 kD, both containing a C-terminal SH2 domain (Pelicci et al., 1992). Adjacent to the SH2 region is a glycine- and proline-rich region. The 2 proteins differ in their N terminals. SHC proteins are involved in mitogenic signal transduction and act by coupling growth factor receptors to the RAS (see 190020) signaling pathway. The protein encoded by the SHC1 gene is thought to act as an adaptor in many signal transduction pathways, for example, facilitating the activation of RAS proteins in response to a variety of factors (Yulug et al., 1995). SHC proteins are rapidly associated with and phosphorylated by growth factor receptors with intrinsic tyrosine kinase activity (McGlade et al., 1992).
In addition to p52 and p46, a 66-kD protein is also encoded by the SHC locus. p66 shares the SH2 domain, a collagen homology domain, and a phosphotyrosine-binding domain. However, p66 contains a unique N-terminal region. Like p52 and p46, p66 becomes tyrosine phosphorylated upon activation of growth factor receptors and forms stable complexes with GRB2 (108355), an adaptor protein for the RAS exchange factor SOS (see 182530). However, it does not affect mitogen-activated protein kinase activity (MAPK) and inhibits c-fos (164810) promoter activation, indicating that p66 may not be involved in RAS activation (Migliaccio et al., 1999).
Nemoto and Finkel (2002) observed that exposure to intracellular reactive oxygen species (ROS) induced an increase in phosphorylated Fkhrl1 (602681) and a shift from a nuclear to a cytosolic localization. They found that serum starvation, a stimulus that increases oxidative stress, resulted in lower levels of hydrogen peroxide in Shc1 -/- cells or in cells expressing a ser36-to-ala (S36A) Shc1 mutant compared with wildtype cells. Serum starvation also increased Fkhrl1-dependent transcriptional activity, which was further augmented in the Shc1-deficient cells. Increased ROS exposure failed to induce increased Fkhrl1 phosphorylation in the mutant cells. Promoter analysis of the catalase (CAT; 115500) gene established the presence of FKHRL1-binding sequences. Reporter assays showed FKHRL1 transactivates CAT, suggesting a capacity to augment antioxidant scavenging. Nemoto and Finkel (2002) concluded that there is an important functional relationship between forkhead proteins (e.g., FKHRL1), SHC1, and intracellular oxidants, all of which are thought to be involved in the aging process in worms and mammals.
The 66-kD isoform of the growth factor adaptor SHC, p66(SHC), translates oxidative damage into cell death by acting as a reactive oxygen species producer within mitochondria. Pinton et al. (2007) demonstrated that protein kinase C-beta (see 176970), activated by oxidative conditions in the cell, induces phosphorylation of p66(SHC) and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase PIN1 (601052). Once imported, p66(Shc) causes alterations of mitochondrial calcium ion responses and 3-dimensional structure, thus causing apoptosis. Pinton et al. (2007) concluded that their data identified a signaling route that activates an apoptotic inducer shortening the life span.
Using quantitative mass spectrometry, Zheng et al. (2013) showed that mammalian Shc1 responds to epidermal growth factor (EGF; 131530) stimulation through multiple waves of distinct phosphorylation events and protein interactions. After stimulation, Shc1 rapidly binds a group of proteins that activate promitogenic or survival pathways dependent on recruitment of the Grb2 (108355) adaptor to Shc1 phosphotyrosine sites. Akt (164730)-mediated feedback phosphorylation of Shc1 ser29 then recruits the Ptpn12 (600079) tyrosine phosphatase. This is followed by interaction with a subnetwork of proteins involved in cytoskeletal reorganization, trafficking, and signal termination that binds Shc1 with delayed kinetics, largely through the SgK269 pseudokinase/adaptor protein (614248). Ptpn12 acts as a switch to convert Shc1 from phosphotyrosine/Grb2-based signaling to the SgK269-mediated pathways that regulate cell invasion and morphogenesis. Zheng et al. (2013) concluded that the Shc1 scaffold therefore directs the temporal flow of signaling information after EGF stimulation.
By Southern analysis of somatic cell hybrids followed by both isotopic and fluorescence in situ hybridization, Huebner et al. (1994) assigned the SHC1 gene to 1q21. Yulug et al. (1995) used fluorescence in situ hybridization to map the SHC1 gene to 1q21. By the same method, an SHC-related sequence (SHCL1; 600739) was mapped to 17q21-q22. By FISH analysis and direct sequencing of vectorette library PCR products, Harun et al. (1997) identified SHC1P1, a 3.2-kb processed pseudogene, in Xq12-q13.1. SHC1P1 is 85% identical to mouse Shc p66.
Almind et al. (1999) sought to determine if genetic variability of the SHC1 isoforms causes a decrease in cell growth and cell differentiation that could be manifested by a decrease in birth weight and length, impaired acute insulin secretion after intravenous glucose, insulin resistance, and eventually a higher prevalence of type II diabetes (125853). By SSCP-heteroduplex analysis of 70 patients with diabetes mellitus, and subsequent nucleotide sequencing of an identified SSCP variant, the authors discovered a met300-to-val (M300V) substitution in the 52-kD isoform. The amino acid variant was predicted to be present in all 3 isoforms of SHC1. In a genotype-phenotype study of 360 young, healthy subjects, the allelic frequency of the M300V allele was 4.2%. In this cohort, no significant differences could be shown between carriers and noncarriers in birth weight and length, the acute insulin response to intravenous glucose, or the insulin sensitivity index, as estimated from an intravenous glucose tolerance test. In an association study of 313 type II diabetic patients and 226 matched glucose-tolerant subjects, there was no significant difference in allelic frequency of the SHC1 variant (5.1% in diabetic patients vs 3.1% in control subjects; P of 0.11). Almind et al. (1999) concluded that by itself, the M300V allele of SHC1 has no major impact on birth weight and length, insulin sensitivity index, acute glucose-induced insulin secretion, or prevalence of random type II diabetes mellitus.
Migliaccio et al. (1999) found that targeted disruption of p66 expression in mice induced stress resistance and prolonged life span. They demonstrated that p66 is serine phosphorylated upon treatment with hydrogen peroxide or irradiation with UV light, and that ablation of p66 enhances cellular resistance to apoptosis induced by hydrogen peroxide or ultraviolet light. A serine phosphorylation-defective mutant of p66 could not restore the normal stress response in p66 -/- cells. The p53 (191170) and p21 (116899) stress response was impaired in p66 -/- cells. p66 -/- mice have increased resistance to paraquat and a 30% increase in life span. Migliaccio et al. (1999) proposed that p66 is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.
Using transgenic Cre/loxP-mediated inducible expression of a phosphorylation-defective Shc mutant and, alternatively, conditional deletion of the Shc gene in mouse thymocytes, Zhang et al. (2002) showed that both expression and tyrosine phosphorylation of Shc have essential roles in thymic T-cell development. They also provided a concise summary of SHC biology.
Almind, K., Ahlgren, M. G., Hansen, T., Urhammer, S. A., Clausen, J. O., Pedersen, O. Discovery of a Met300Val variant in Shc and studies of its relationship to birth weight and length, impaired insulin secretion, insulin resistance, and type 2 diabetes mellitus. J. Clin. Endocr. Metab. 84: 2241-2244, 1999. [PubMed: 10372739] [Full Text: https://doi.org/10.1210/jcem.84.6.5713]
Harun, R. B., Smith, K. K., Leek, J. P., Markham, A. F., Norris, A., Morrison, J. F. J. Characterization of human SHC p66 cDNA and its processed pseudogene mapping to Xq12-q13.1. Genomics 42: 349-352, 1997. [PubMed: 9192859] [Full Text: https://doi.org/10.1006/geno.1997.4728]
Huebner, K., Kastury, K., Druck, T., Salcini, A. E., Lanfrancone, L., Pelicci, G., Lowenstein, E., Li, W., Park, S.-H., Cannizzaro, L., Pelicci, P. G., Schlessinger, J. Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2). Genomics 22: 281-287, 1994. [PubMed: 7806213] [Full Text: https://doi.org/10.1006/geno.1994.1385]
McGlade, J., Cheng, A., Pelicci, G., Pelicci, P. G., Pawson, T. Shc proteins are phosphorylated and regulated by the v-src and v-fps protein-tyrosine-kinases. Proc. Nat. Acad. Sci. 89: 8869-8873, 1992. [PubMed: 1409579] [Full Text: https://doi.org/10.1073/pnas.89.19.8869]
Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandolfi, P. P., Lanfrancone, L., Pelicci, P. G. The p66(shc) adaptor protein controls oxidative stress response and life span in mammals. Nature 402: 309-313, 1999. [PubMed: 10580504] [Full Text: https://doi.org/10.1038/46311]
Nemoto, S., Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295: 2450-2452, 2002. [PubMed: 11884717] [Full Text: https://doi.org/10.1126/science.1069004]
Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J., Cavallo, F., Forni, G., Nicoletti, I., Grignani, F., Pawson, T., Pelicci, P. G. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70: 93-104, 1992. [PubMed: 1623525] [Full Text: https://doi.org/10.1016/0092-8674(92)90536-l]
Pinton, P., Rimessi, A., Marchi, S., Orsini, F., Migliaccio, E., Giorgio, M., Contursi, C., Minucci, S., Mantovani, F., Wieckowski, M. R., Del Sal, G., Pelicci, P. G., Rizzuto, R. Protein kinase C-beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66(Shc) Science 315: 659-663, 2007. [PubMed: 17272725] [Full Text: https://doi.org/10.1126/science.1135380]
Yulug, I. G., Egan, S. E., See, C. G., Fisher, E. M. C. A human SHC-related sequence maps to chromosome 17, the SHC gene maps to chromosome 1. Hum. Genet. 96: 245-248, 1995. [PubMed: 7635484] [Full Text: https://doi.org/10.1007/BF00207393]
Zhang, L., Camerini, V., Bender, T. P., Ravichandran, K. S. A nonredundant role for the adapter protein Shc in thymic T cell development. Nature Immun. 3: 749-755, 2002. [PubMed: 12101399] [Full Text: https://doi.org/10.1038/ni820]
Zheng, Y., Zhang, C., Croucher, D. R., Soliman, M. A., St-Denis, N., Pasculescu, A., Taylor, L., Tate, S. A., Hardy, W. R., Colwill, K., Dai, A. Y., Bagshaw, R., Dennis, J. W., Gingras, A.-C., Daly, R. J., Pawson, T. Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature 499: 166-171, 2013. [PubMed: 23846654] [Full Text: https://doi.org/10.1038/nature12308]