Disease relevance of SHC1

• The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer [1].
• A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells [2].
• Mice inoculated intradermally with 10(8) plaque-forming units of the vaccinia/RT vector developed specific antibodies to the p66/51 proteins of HIV, but anti-HIV antibodies were not detected in mice inoculated with the vaccinia/gag vector [3].
• Furthermore, the expression of Shc in a gastric cancer cell line, MKN 28, was also studied. p66 Shc was not detected at all in gastric cancer or the adjacent normal mucosa [4].
• Expression and activation of SHC/MAP kinase pathway in primary acute myeloid leukemia blasts [5].

Psychiatry related information on SHC1

• The effects of the SHCP on selected aspects of decision-making among fifth graders [6].

High impact information on SHC1

• The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response [7].
• A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction [8].
• Anti-SHC antibodies recognized three proteins of 46, 52, and 66 kd in a wide range of mammalian cell lines [8].
• NIH 3T3 mouse fibroblasts that constitutively overexpressed SHC acquired a transformed phenotype in culture and formed tumors in nude mice [8].
• The SHC cDNA is predicted to encode overlapping proteins of 46.8 and 51.7 kd that contain a single C-terminal SH2 domain, and an adjacent glycine/proline-rich motif with regions of homology with the alpha 1 chain of collagen, but no identifiable catalytic domain [8].

Chemical compound and disease context of SHC1

• Alanine-scanning mutations in the "primer grip" of p66 HIV-1 reverse transcriptase result in selective loss of RNA priming activity [9].
• Cross-linking experiments were performed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutants with unique cysteine residues at several positions (positions 65, 67, 70, and 74) in the fingers subdomain of the p66 subunit [10].
• Here we show that antagonistic activity can be conferred to peptides of HIV envelope glycoprotein gp120 and reverse transcriptase p66 by adding flanking polypeptide sequences at the C or at the N terminus by genetic engineering, rather than by introducing substitutions by synthesis [11].
• Antibody responses to p66, a candidate integrin ligand of Borrelia burgdorferi, were studied in 79 patients with early or late manifestations of Lyme disease [12].
• A binding site for TSAO-m(3)T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of "classical" HIV-1 non-nucleoside inhibitors is proposed [13].

Biological context of SHC1

• A genotype combination analysis of the non-synonymous polymorphisms in the IRS1, IRS2 and SHC1 genes did not show any effect on breast cancer risk [1].
• Both SHC1 and GRB2 are in chromosome regions that may be duplicated in some tumor types [14].
• We identified 12 single nucleotide polymorphisms (SNPs) within a 10-kb region encompassing the entire SHC1 gene from the DNA of 30 centenarians and 24 healthy younger controls [15].
• We investigated the possible association of SHC1 with longevity using association analyses with allelotypes and haplotypes but found that the SNPs identified in SHC1 had no impact on longevity for Japanese centenarians [15].
• The increase in SHC tyrosine phosphorylation and MAPK stimulation through both Gq- and Gi-coupled receptors was reduced strongly upon selective inhibition of EGFR function [16].

Anatomical context of SHC1

• Involvement of SHC, GRB2, SOS and RAS in prolactin signal transduction in mammary epithelial cells [17].
• The two prominent tyrosine-phosphorylated proteins are p52SHC and p115CBL in myeloid cell lines and p52SHC and an uncharacterized p115 in early B cell lines [18].
• Transduction of a mitogenic signal from the cell membrane to the nucleus involves the adapter proteins SHC and Grb2, which mediate activation of the Ras/mitogen-activated protein (MAP) kinase pathway [19].
• p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells [20].
• Human GH was shown to promote the rapid tyrosyl phosphorylation of 66-, 52-, and 46-kDa SHC proteins in 3T3-F442A fibroblasts [21].

Associations of SHC1 with chemical compounds

• SHC contains two phosphotyrosine interaction domains: a PTB (Phosphotyrosine Binding) and a SH2 (Src Homology 2) domain [22].
• Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation [23].
• Treatment of WB cells with hormones linked to Ca2+ mobilization and protein kinase C (PKC) activation, including angiotensin II, [Arg8]vasopressin, or epinephrine, stimulated rapid (less than or equal to 15-s) and transient increases in the P-Tyr content of several proteins (p120/125, p75/78, and p66) [24].
• Within 2 min of stimulation, we also observed increased tyrosine phosphorylation of SHC, activation of the guanidine nucleotide exchange activity on p21(ras), and an electrophoretic mobility shift of MAP kinase [25].
• The SH2 domain interaction with CD45 was specific as glutathione S-transferase-SH2 fusion proteins from p85 alpha subunit of phosphatidylinositol 3-kinase and SHC did not bind to CD45 [26].

Physical interactions of SHC1

• Analyses by site directed-mutagenesis revealed that it binds to tyrosine 1062 in RET that is also known to be a binding site for the SHC adaptor protein [27].
• The SH2 domain of CRK bound to the SHC protein phosphorylated on tyrosine residues by NGF stimulation [28].
• In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR [29].
• We have shown previously that Taxol activates ERK 1/2 MAP-kinases and results in the formation of GRB2/SHC complexes in murine macrophage-like RAW 267.4 cells [30].
• EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized [31].

Enzymatic interactions of SHC1

• Previous studies have shown that SHC proteins are phosphorylated on Y239/Y240 and Y313 (Y317 in humans) by tyrosine kinases such as the EGF and IL3 receptors [22].
• SHC was tyrosine phosphorylated in response to Fc gamma RI stimulation of U937IF cells and bound to the SH2 domain of GRB2 in a stimulation-dependent manner [32].
• We examined the classical signal pathway in which SHC is phosphorylated and binds to SOS and GRB-2 to activate Ras, Raf, and MAP kinase [33].
• Also the SHC-derived SH2 domain formed complexes with the tyrosine-phosphorylated Ig-alpha/beta heterodimer, while the C- and N-terminal SH2 domains of GTPase-activating protein displayed completely different binding preferences [34].

Regulatory relationships of SHC1

• Taken together, the present data show that SHC can antagonize cell proliferation induced by FLT3 stimulation and regulate phosphorylation of the SHIP negative regulator [35].
• We show that phosphatidylinositol 3'-kinase (PI3K) and SHC bind to the HRG-activated ErbB3 in myotubes [36].
• Despite reports that p66 Shc can negatively regulate epidermal growth factor signaling to the mitogen-activated protein kinase pathway, we found no change in epidermal growth factor-stimulated activation of mitogen-activated protein kinase in the F-11 cell line [37].

Other interactions of SHC1

• In contrast, under the same treatment, tyrosine phosphorylation of Src-homology/collagen proteins (SHC; another substrate of the IGF-IR) and SHC/GRB2 binding were elevated [38].
• The protein levels of the IGF-IR and IRS-1 were not modified by Tam, whereas SHC protein expression was either not affected or moderately decreased by the treatment [38].
• Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling [22].
• IRS1, IRS2 and SHC1 are the key mediators for the downstream pathway processes [1].
• Additionally, NCK and SHC genes were more narrowly localized by chromosomal in situ hybridization [14].

Analytical, diagnostic and therapeutic context of SHC1

• These proteins included constitutively phosphorylated Janus kinase 2, signal transducer and activator of transcription 5, and SHC [39].
• 1. This novel SHC-related sequence was characterized by direct sequencing of vectorette library PCR products produced from clone 20D11B [40].
• Sequence analysis demonstrated the presence of multiple stop codons identifying this isoform of SHC as a processed pseudogene [40].
• The membrane-distal region, which contains the major sites of tyrosine phosphorylation, is required for phosphorylation of SHC and p85, not for mitogenesis, thus allowing functional dissection of the signaling pathways activated by cytokines [41].
• Insulin stimulated tyrosine phosphorylation of SHC, a SH2 containing protein, was demonstrated in Chinese hamster ovary cells overexpressing the insulin receptor by immunoblotting with antiphosphotyrosine antibodies and in vivo labeling [42].

References