TY - JOUR
T1 - A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction
AU - Pelicci, Giuliana
AU - Lanfrancone, Luisa
AU - Grignani, Francesco
AU - McGlade, Jane
AU - Cavallo, Federica
AU - Forni, Guido
AU - Nicoletti, Ildo
AU - Grignani, Fausto
AU - Pawson, Tony
AU - Giuseppe Pelicci, Pier
N1 - Funding Information:
transformation, colony formation in semisolid medium, and tumor formation following injection into nude mice. The mechanism by which SHC transforms cells is of interest. SHC is similar to v-Ok, in that it lacks an obvious catalytic domain, and may therefore function by activating associated signaling subunits. However, in contrast with v-Crk, we have not seen a marked increase in phosphotyrosine-containing proteins in SHC transformed cells (unpublished data). The SHC gene in the leukemic cells from which the SHC cDNA was derived is not detectably rearranged compared with the SHC genomic locus in normal, germline DNA (unpublished data). It therefore appears likely that SHC-induced transformation of mouse fibroblasts is due to the overexpression of structurally normal SHC proteins. This notion is supported by the correlation between SHC expression levels and the degree of malignancy in SHC-transfected fibroblasts. If the SHC proteins are normally involved in transmitting a mitogenic signal from activated growth factor receptors, it is possible that their overexpression induces the constitutive stimulation of an SHC-regulated mitogenic pathway. The obsetva-tion that SHC is a substrate for normal receptor tyrosine kinases and can transform cells when overexpressed, raises the possibility that SHC might participate in the transforming activity of oncogenic tyrosine kinases. Indeed we find that SHC is highly tyrosine phosphorylated in cells transformed by v&c, v-fps, or an oncogenic variant of neu (unpublished data). In addition, SHC proteins associate with the PDGFR and show modest increase in tyrosine phosphorylation in PDGF-stimulated cells (unpublished data). To explain the biological effects of SHC in signal transduction in normal and transformed cells, it will be important to identify its presumptive downstream targets. .
PY - 1992/7/10
Y1 - 1992/7/10
N2 - A new SH2-containing sequence, SHC, was isolated by screening cDNA libraries with SH2 representative DNA probes. 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 α1 chain of collagen, but no identifiable catalytic domain. Anti-SHC antibodies recognized three proteins of 46, 52, and 66 kd in a wide range of mammalian cell lines. These SHC proteins complexed with and were phosphorylated by activated epidermal growth factor receptor. The physical association of SHC proteins with activated receptors was recreated in vitro by using a bacterially expressed SHC SH2 domain. NIH 3T3 mouse fibroblasts that constitutively overexpressed SHC acquired a transformed phenotype in culture and formed tumors in nude mice. These results suggest that the SHC gene products couple activated growth factor receptors to a signaling pathway that regulates the proliferation of mammalian cells.
AB - A new SH2-containing sequence, SHC, was isolated by screening cDNA libraries with SH2 representative DNA probes. 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 α1 chain of collagen, but no identifiable catalytic domain. Anti-SHC antibodies recognized three proteins of 46, 52, and 66 kd in a wide range of mammalian cell lines. These SHC proteins complexed with and were phosphorylated by activated epidermal growth factor receptor. The physical association of SHC proteins with activated receptors was recreated in vitro by using a bacterially expressed SHC SH2 domain. NIH 3T3 mouse fibroblasts that constitutively overexpressed SHC acquired a transformed phenotype in culture and formed tumors in nude mice. These results suggest that the SHC gene products couple activated growth factor receptors to a signaling pathway that regulates the proliferation of mammalian cells.
UR - http://www.scopus.com/inward/record.url?scp=0026777369&partnerID=8YFLogxK
U2 - 10.1016/0092-8674(92)90536-L
DO - 10.1016/0092-8674(92)90536-L
M3 - Article
SN - 0092-8674
VL - 70
SP - 93
EP - 104
JO - Cell
JF - Cell
IS - 1
ER -