Atlas of Genetics and Cytogenetics in Oncology and Haematology


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SHC1 (SHC (Src homology 2 domain containing) transforming protein 1)

Identity

Other namesFLJ26504
OTTHUMP00000035409
OTTHUMP00000035471
SHC
SHCA
p66
HGNC (Hugo) SHC1
LocusID (NCBI) 6464
Location 1q21.3
Location_base_pair Starts at 154934774 and ends at 154943223 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Mapping of SHC1 gene on genomic context of the human chromosome 1.
Note SHC1 is the first discovered and the most studied member of the Shc signal transducer protein family. The other three members of the Shc-family are SHC2 (also known as SLI, SHCB or SCK), SHC3 (RAI, SHCC or N-SHC) and SHC4 (RALP or SHCD). Unlike SHC1, that is ubiquitously expressed, the other Shc paralogous show restricted expression pattern. In general Shc proteins function as phosphotyrosine adaptor molecules in various receptor-mediated signaling pathways and each member seems to be specialized to contribute in different manner to critical cellular functions such as proliferation, survival, regulation of oxidative stress, tissue morphogenesis, cell migration and apoptosis. Moreover in murine models, a genetic deficiency of the p66 (Shc) (the longest isoform of SHC1 gene products) extends life span by 30% and confers resistance to oxidative stress.

DNA/RNA

 
  SHC1 locus organization and alternative splicing isoforms. Dark blue boxes correspond to CDS; light blue portions represent 5' and 3' UTR respectively; red triangles point to the first ATG codon of p66, p52 and p46 isoforms in that order.
Description SHC1 gene covers 12,066 bp of DNA on q21.3 arm of chr1 and counts 13 exons and 13 introns.
Transcription 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.
Pseudogene Two possible processed pseudogenes of SHC1 are located on chrX and chr17.

Protein

 
  Modular domain organization of the three SHC1 protein isoforms.
Description 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.
Expression 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 forebrain's 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.
Localisation 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.
Function 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.
 
  Schematic description of different contribution of SHC1 proteins in survival and apoptosis. Upon growth factor (GF) stimulation p52Shc binds to activated receptor (RTKs) becomes phosphorylated and binds to Grb2-Sos complex. The translocation of Grab2/SOS complex from the cytosol to the cellular membrane induces Ras activation that in turn leads to MAP kinase/Erk pathway triggering that finally regulates cell proliferation and/or differentiation. Pro-apoptotic signals, instead, induce p66Shc release from a putative inhibitory complex (Tim -Tom mitochondrial import complex) on mitochondria. Activated p66Shc then reduces cytochrome c and generates hydrogen peroxide (H2O2) that leads to permeability transition pore (PTP) opening, mitochondrial swelling, cytochrome c release, caspase activation and apoptosis.
Homology 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.

Mutations

Note The SHC1 gene's 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.

Implicated in

Entity Cancers (indirect)
Note P52/p46 proteins are implicated in cell proliferation and carcinogenesis.
The p52Shc and p46Shc isoforms of Shc are overexpressed or hyper-phosphorylated in many tumor types where known Tyrosine kinases Receptors are constitutively activated.
Constitutively activated p52Shc Human tumor cell lines Constitutively activated receptor
  Vulval carcinoma, Bladder carcinoma, Neuroblastoma Hepatocarcinoma EGFR
  Stomach carcinoma Met
  Lung carcinoma ErbB2
  Chronic myeloid Leukaemia Bcr-abl
  Thyroid carcinoma Ret
  Pancreatic carcinoma PDGFR
Recently was demonstrated that SHC1 is a crucial determinant of the Neu/ErbB-2 -TGFb cooperation signaling that promotes breast cancer cell motility and invasion.
The involvement of p66Shc in tumorigenesis is still controversial. Altered levels of p66Shc were reported to be found in some tumors but the results seem contradictory. In the breast cancer cells and primary tumors p66Shc was described to be both over-expressed and down-regulated. Indeed the ablation of p66Shc does not increase spontaneous or induced tumor incidence in mice. P66Shc adaptor protein may have a potential implication in the pathophysiology of aging.
  

External links

Nomenclature
HGNC (Hugo)SHC1   10840
Cards
AtlasSHC1ID42287ch1q21
Entrez_Gene (NCBI)SHC1  6464  SHC (Src homology 2 domain containing) transforming protein 1
GeneCards (Weizmann)SHC1
Ensembl (Hinxton)ENSG00000160691 [Gene_View]  chr1:154934774-154943223 [Contig_View]  SHC1 [Vega]
ICGC DataPortalENSG00000160691
AceView (NCBI)SHC1
Genatlas (Paris)SHC1
WikiGenes6464
SOURCE (Princeton)NM_001130040 NM_001130041 NM_001202859 NM_003029 NM_183001
Genomic and cartography
GoldenPath (UCSC)SHC1  -  1q21.3   chr1:154934774-154943223 -  1q21   [Description]    (hg19-Feb_2009)
EnsemblSHC1 - 1q21 [CytoView]
Mapping of homologs : NCBISHC1 [Mapview]
OMIM600560   
Gene and transcription
Genbank (Entrez)AB208849 AB451255 AB451379 AK096169 AK130014
RefSeq transcript (Entrez)NM_001130040 NM_001130041 NM_001202859 NM_003029 NM_183001
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_029028 NT_004487 NW_001838531 NW_004929293
Consensus coding sequences : CCDS (NCBI)SHC1
Cluster EST : UnigeneHs.433795 [ NCBI ]
CGAP (NCI)Hs.433795
Alternative Splicing : Fast-db (Paris)GSHG0002575
Alternative Splicing GalleryENSG00000160691
Gene ExpressionSHC1 [ NCBI-GEO ]     SHC1 [ SEEK ]   SHC1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP29353 (Uniprot)
NextProtP29353  [Medical]
With graphics : InterProP29353
Splice isoforms : SwissVarP29353 (Swissvar)
Domaine pattern : Prosite (Expaxy)PID (PS01179)    SH2 (PS50001)   
Domains : Interpro (EBI)PH_like_dom    PID_Shc-like    PTB/PI_dom    SH2   
Related proteins : CluSTrP29353
Domain families : Pfam (Sanger)PID (PF00640)    SH2 (PF00017)   
Domain families : Pfam (NCBI)pfam00640    pfam00017   
Domain families : Smart (EMBL)PTB (SM00462)  SH2 (SM00252)  
DMDM Disease mutations6464
Blocks (Seattle)P29353
PDB (SRS)1MIL    1N3H    1OY2    1QG1    1SHC    1TCE    1WCP    2L1C    4JMH   
PDB (PDBSum)1MIL    1N3H    1OY2    1QG1    1SHC    1TCE    1WCP    2L1C    4JMH   
PDB (IMB)1MIL    1N3H    1OY2    1QG1    1SHC    1TCE    1WCP    2L1C    4JMH   
PDB (RSDB)1MIL    1N3H    1OY2    1QG1    1SHC    1TCE    1WCP    2L1C    4JMH   
Human Protein AtlasENSG00000160691
Peptide AtlasP29353
HPRD02780
IPIIPI00643176   IPI01014876   IPI00943132   IPI00021326   IPI00973146   IPI00165135   IPI00513796   IPI00643863   IPI00641285   IPI00647867   IPI00640190   
Protein Interaction databases
DIP (DOE-UCLA)P29353
IntAct (EBI)P29353
FunCoupENSG00000160691
BioGRIDSHC1
IntegromeDBSHC1
STRING (EMBL)SHC1
Ontologies - Pathways
QuickGOP29353
Ontology : AmiGOMAPK cascade  activation of MAPK activity  angiogenesis  protein tyrosine kinase activity  transmembrane receptor protein tyrosine kinase adaptor activity  epidermal growth factor receptor binding  insulin receptor binding  insulin-like growth factor receptor binding  neurotrophin TRKA receptor binding  protein binding  phospholipid binding  mitochondrial matrix  cytosol  plasma membrane  plasma membrane  activation of signaling protein activity involved in unfolded protein response  epidermal growth factor receptor signaling pathway  regulation of epidermal growth factor-activated receptor activity  Ras protein signal transduction  heart development  blood coagulation  positive regulation of cell proliferation  insulin receptor signaling pathway  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  single organismal cell-cell adhesion  peptidyl-tyrosine phosphorylation  platelet activation  endoplasmic reticulum unfolded protein response  actin cytoskeleton reorganization  Fc-epsilon receptor signaling pathway  regulation of growth  cellular protein metabolic process  innate immune response  positive regulation of DNA replication  ephrin receptor binding  neurotrophin TRK receptor signaling pathway  leukocyte migration  Shc-EGFR complex  
Ontology : EGO-EBIMAPK cascade  activation of MAPK activity  angiogenesis  protein tyrosine kinase activity  transmembrane receptor protein tyrosine kinase adaptor activity  epidermal growth factor receptor binding  insulin receptor binding  insulin-like growth factor receptor binding  neurotrophin TRKA receptor binding  protein binding  phospholipid binding  mitochondrial matrix  cytosol  plasma membrane  plasma membrane  activation of signaling protein activity involved in unfolded protein response  epidermal growth factor receptor signaling pathway  regulation of epidermal growth factor-activated receptor activity  Ras protein signal transduction  heart development  blood coagulation  positive regulation of cell proliferation  insulin receptor signaling pathway  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  single organismal cell-cell adhesion  peptidyl-tyrosine phosphorylation  platelet activation  endoplasmic reticulum unfolded protein response  actin cytoskeleton reorganization  Fc-epsilon receptor signaling pathway  regulation of growth  cellular protein metabolic process  innate immune response  positive regulation of DNA replication  ephrin receptor binding  neurotrophin TRK receptor signaling pathway  leukocyte migration  Shc-EGFR complex  
Pathways : BIOCARTAEPO Signaling Pathway [Genes]    IL 4 signaling pathway [Genes]    BCR Signaling Pathway [Genes]    Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia [Genes]    IGF-1 Signaling Pathway [Genes]    PDGF Signaling Pathway [Genes]    VEGF, Hypoxia, and Angiogenesis [Genes]    TPO Signaling Pathway [Genes]    IL 2 signaling pathway [Genes]    p38 MAPK Signaling Pathway [Genes]    Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling [Genes]    Integrin Signaling Pathway [Genes]    Calcium Signaling by HBx of Hepatitis B virus [Genes]    Bioactive Peptide Induced Signaling Pathway [Genes]    Growth Hormone Signaling Pathway [Genes]    IL 6 signaling pathway [Genes]    Trefoil Factors Initiate Mucosal Healing [Genes]    EGF Signaling Pathway [Genes]    Role of Erk5 in Neuronal Survival [Genes]    MAPKinase Signaling Pathway [Genes]    Links between Pyk2 and Map Kinases [Genes]    Fc Epsilon Receptor I Signaling in Mast Cells [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    Insulin Signaling Pathway [Genes]    Nerve growth factor pathway (NGF) [Genes]    PTEN dependent cell cycle arrest and apoptosis [Genes]    T Cell Receptor Signaling Pathway [Genes]    Trka Receptor Signaling Pathway [Genes]    Erk1/Erk2 Mapk Signaling pathway [Genes]    Role of ERBB2 in Signal Transduction and Oncology [Genes]    Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation [Genes]    IL 3 signaling pathway [Genes]    The IGF-1 Receptor and Longevity [Genes]    Sprouty regulation of tyrosine kinase signals [Genes]   
Pathways : KEGGErbB signaling pathway    Ras signaling pathway    Chemokine signaling pathway    Focal adhesion    Natural killer cell mediated cytotoxicity    Neurotrophin signaling pathway    Insulin signaling pathway    Estrogen signaling pathway    Prolactin signaling pathway    Alcoholism    Bacterial invasion of epithelial cells    MicroRNAs in cancer    Glioma    Chronic myeloid leukemia   
REACTOMEP29353 [protein]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_604 Hemostasis [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
REACTOME PathwaysREACT_17015 Metabolism of proteins [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseSHC1
Wikipedia pathwaysSHC1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SHC1
SNP (GeneSNP Utah)SHC1
SNP : HGBaseSHC1
Genetic variants : HAPMAPSHC1
1000_GenomesSHC1 
ICGC programENSG00000160691 
CONAN: Copy Number AnalysisSHC1 
Somatic Mutations in Cancer : COSMICSHC1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)1:154934774-154943223
Mutations and Diseases : HGMDSHC1
OMIM600560   
MedgenSHC1
GENETestsSHC1
Disease Genetic AssociationSHC1
Huge Navigator SHC1 [HugePedia]  SHC1 [HugeCancerGEM]
Genomic VariantsSHC1  SHC1 [DGVbeta]
Exome VariantSHC1
dbVarSHC1
ClinVarSHC1
snp3D : Map Gene to Disease6464
General knowledge
Homologs : HomoloGeneSHC1
Homology/Alignments : Family Browser (UCSC)SHC1
Phylogenetic Trees/Animal Genes : TreeFamSHC1
Chemical/Protein Interactions : CTD6464
Chemical/Pharm GKB GenePA35746
Clinical trialSHC1
Cancer Resource (Charite)ENSG00000160691
Other databases
Other databaseBioGRID: Shc1
Other databaseGenetic Association Database
Probes
Litterature
PubMed384 Pubmed reference(s) in Entrez
CoreMineSHC1
GoPubMedSHC1
iHOPSHC1

Bibliography

A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.
Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG.
Cell. 1992 Jul 10;70(1):93-104.
PMID 1623525
 
Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.
Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, et al.
Nature. 1992 Dec 17;360(6405):689-92.
PMID 1465135
 
Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation.
Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA.
Nature. 1993 May 6;363(6424):45-51.
PMID 8479536
 
Interaction of Shc with the zeta chain of the T cell receptor upon T cell activation.
Ravichandran KS, Lee KK, Songyang Z, Cantley LC, Burn P, Burakoff SJ.
Science. 1993 Nov 5;262(5135):902-5.
PMID 8235613
 
Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling.
Sato N, Sakamaki K, Terada N, Arai K, Miyajima A.
EMBO J. 1993 Nov;12(11):4181-9.
PMID 8223433
 
Shc products are substrates of erbB-2 kinase.
Segatto O, Pelicci G, Giuli S, Digiesi G, Di Fiore PP, McGlade J, Pawson T, Pelicci PG.
Oncogene. 1993 Aug;8(8):2105-12.
PMID 8101647
 
The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J.
Science. 1993 Jun 25;260(5116):1953-5.
PMID 8316835
 
Identification of Src, Fyn, and Lyn SH3-binding proteins: implications for a function of SH3 domains.
Weng Z, Thomas SM, Rickles RJ, Taylor JA, Brauer AW, Seidel-Dugan C, Michael WM, Dreyfuss G, Brugge JS.
Mol Cell Biol. 1994 Jul;14(7):4509-21.
PMID 7516469
 
Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes.
Mainiero F, Pepe A, Wary KK, Spinardi L, Mohammadi M, Schlessinger J, Giancotti FG.
EMBO J. 1995 Sep 15;14(18):4470-81.
PMID 7556090
 
Constitutive phosphorylation of Shc proteins in human tumors.
Pelicci G, Lanfrancone L, Salcini AE, Romano A, Mele S, Grazia Borrello M, Segatto O, Di Fiore PP, Pelicci PG.
Oncogene. 1995 Sep 7;11(5):899-907.
PMID 7675449
 
Structure and ligand recognition of the phosphotyrosine binding domain of Shc.
Zhou MM, Ravichandran KS, Olejniczak EF, Petros AM, Meadows RP, Sattler M, Harlan JE, Wade WS, Burakoff SJ, Fesik SW.
Nature. 1995 Dec 7;378(6557):584-92.
PMID 8524391
 
Not all Shc's roads lead to Ras.
Bonfini L, Migliaccio E, Pelicci G, Lanfrancone L, Pelicci PG.
Trends Biochem Sci. 1996 Jul;21(7):257-61.
PMID 8755247
 
Shc proteins are localized on endoplasmic reticulum membranes and are redistributed after tyrosine kinase receptor activation.
Lotti LV, Lanfrancone L, Migliaccio E, Zompetta C, Pelicci G, Salcini AE, Falini B, Pelicci PG, Torrisi MR.
Mol Cell Biol. 1996 May;16(5):1946-54.
PMID 8628261
 
A family of Shc related proteins with conserved PTB, CH1 and SH2 regions.
Pelicci G, Dente L, De Giuseppe A, Verducci-Galletti B, Giuli S, Mele S, Vetriani C, Giorgio M, Pandolfi PP, Cesareni G, Pelicci PG.
Oncogene. 1996 Aug 1;13(3):633-41.
PMID 8760305
 
The adaptor protein Shc couples a class of integrins to the control of cell cycle progression.
Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG.
Cell. 1996 Nov 15;87(4):733-43.
PMID 8929541
 
Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway.
Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KM, Superti-Furga G, Pawson T, Di Fiore PP, Lanfrancone L, Pelicci PG.
EMBO J. 1997 Feb 17;16(4):706-16.
PMID 9049300
 
The 66-kDa Shc isoform is a negative regulator of the epidermal growth factor-stimulated mitogen-activated protein kinase pathway.
Okada S, Kao AW, Ceresa BP, Blaikie P, Margolis B, Pessin JE.
J Biol Chem. 1997 Oct 31;272(44):28042-9.
PMID 9346957
 
A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth.
Wary KK, Mariotti A, Zurzolo C, Giancotti FG.
Cell. 1998 Sep 4;94(5):625-34.
PMID 9741627
 
Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc.
Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY.
J Biol Chem. 1999 Jun 25;274(26):18393-400.
PMID 10373445
 
The p66shc adaptor protein controls oxidative stress response and life span in mammals.
Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG.
Nature. 1999 Nov 18;402(6759):309-13.
PMID 10580504
 
The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo.
Lai KM, Pawson T.
Genes Dev. 2000 May 1;14(9):1132-45.
PMID 10809671
 
Evolution of Shc functions from nematode to human.
Luzi L, Confalonieri S, Di Fiore PP, Pelicci PG.
Curr Opin Genet Dev. 2000 Dec;10(6):668-74.
PMID 11088019
 
Shc signaling in differentiating neural progenitor cells.
Conti L, Sipione S, Magrassi L, Bonfanti L, Rigamonti D, Pettirossi V, Peschanski M, Haddad B, Pelicci P, Milanesi G, Pelicci G, Cattaneo E.
Nat Neurosci. 2001 Jun;4(6):579-86.
PMID 11369938
 
Serine/threonine phosphorylation of ShcA. Regulation of protein-tyrosine phosphatase-pest binding and involvement in insulin signaling.
Faisal A, el-Shemerly M, Hess D, Nagamine Y.
J Biol Chem. 2002 Aug 16;277(33):30144-52. Epub 2002 Jun 6.
PMID 12052829
 
The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathway.
Pelicci G, Troglio F, Bodini A, Melillo RM, Pettirossi V, Coda L, De Giuseppe A, Santoro M, Pelicci PG.
Mol Cell Biol. 2002 Oct;22(20):7351-63.
PMID 12242309
 
The p66Shc longevity gene is silenced through epigenetic modifications of an alternative promoter.
Ventura A, Luzi L, Pacini S, Baldari CT, Pelicci PG.
J Biol Chem. 2002 Jun 21;277(25):22370-6. Epub 2002 Apr 10.
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Variation in the SHC1 gene and longevity in humans.
Mooijaart SP, van Heemst D, Schreuder J, van Gerwen S, Beekman M, Brandt BW, Eline Slagboom P, Westendorp RG; 'Long Life' Study Group.
Exp Gerontol. 2004 Feb;39(2):263-8.
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The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential.
Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, Giorgio M, Pelicci PG.
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The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer.
Wagner K, Hemminki K, Grzybowska E, Klaes R, Butkiewicz D, Pamula J, Pekala W, Zientek H, Mielzynska D, Siwinska E, Forsti A.
Carcinogenesis. 2004 Dec;25(12):2473-8. Epub 2004 Aug 12.
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Enhanced expression of p46 Shc in the nucleus and p52 Shc in the cytoplasm of human gastric cancer.
Yukimasa S, Masaki T, Yoshida S, Uchida N, Watanabe S, Usuki H, Yoshiji H, Maeta T, Ebara K, Nakatsu T, Kurokohchi K, Kuriyama S.
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Apoptosis and aging: role of p66Shc redox protein.
Migliaccio E, Giorgio M, Pelicci PG.
Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):600-8. (REVIEW)
PMID 16677103
 
Regulatory effects of the mitochondrial energetic status on mitochondrial p66Shc.
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Biol Chem. 2006 Oct-Nov;387(10-11):1405-10.
PMID 17081113
 
Mitochondrial DNA copy number is regulated by cellular proliferation: a role for Ras and p66(Shc).
Trinei M, Berniakovich I, Pelicci PG, Giorgio M.
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):624-30. Epub 2006 May 25.
PMID 16829231
 
RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas.
Fagiani E, Giardina G, Luzi L, Cesaroni M, Quarto M, Capra M, Germano G, Bono M, Capillo M, Pelicci P, Lanfrancone L.
Cancer Res. 2007 Apr 1;67(7):3064-73.
PMID 17409413
 
Combinatorial ShcA docking interactions support diversity in tissue morphogenesis.
Hardy WR, Li L, Wang Z, Sedy J, Fawcett J, Frank E, Kucera J, Pawson T.
Science. 2007 Jul 13;317(5835):251-6.
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Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase.
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Mol Cell Biol. 2007 Jul;27(13):4759-73. Epub 2007 Apr 23.
PMID 17452444
 
p66Shc-generated oxidative signal promotes fat accumulation.
Berniakovich I, Trinei M, Stendardo M, Migliaccio E, Minucci S, Bernardi P, Pelicci PG, Giorgio M.
J Biol Chem. 2008 Dec 5;283(49):34283-93. Epub 2008 Oct 6.
PMID 18838380
 
Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation.
Liu Y, Sweet DT, Irani-Tehrani M, Maeda N, Tzima E.
J Cell Biol. 2008 Jul 14;182(1):185-96. Epub 2008 Jul 7.
PMID 18606845
 
Signaling through ShcA is required for transforming growth factor beta- and Neu/ErbB-2-induced breast cancer cell motility and invasion.
Northey JJ, Chmielecki J, Ngan E, Russo C, Annis MG, Muller WJ, Siegel PM.
Mol Cell Biol. 2008 May;28(10):3162-76. Epub 2008 Mar 10.
PMID 18332126
 
Spatial signaling networks converge at the adaptor protein Shc.
Sweet DT, Tzima E.
Cell Cycle. 2009 Jan 15;8(2):231-5. Epub 2009 Jan 10.
PMID 19164921
 
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Contributor(s)

Written02-2009Lucilla Luzi, Enrica Migliaccio, Pier Giuseppe Pelicci
IFOM, FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139 Milano, Italy (LL); EIO, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy (EM, PGP)

Citation

This paper should be referenced as such :
Luzi, L ; Migliaccio, E ; Pelicci, PG
SHC1 (SHC (Src homology 2 domain containing) transforming protein 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(1):-.
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