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A family of Shc related proteins with conserved PTB, CH1 and SH2 regions
G Pelicci1, L Dente, A De Giuseppe
1Istituto Europeo di Oncologia, Dpt. of Experimental Oncology, Milan, Italy.
Abstract:
Shc proteins are targets of activated tyrosine kinases and have been implicated in the transmission of activation signals to Ras. Upon phosphorylation, Shc proteins form stable complexes with cellular tyrosine-phosphorylated proteins and with the Grb2 adaptor protein. Two Shc isoforms of 52 and 46 kDa have been characterized. They share a C-terminal SH2 domain, a proline- and glycine-rich region (collagen homologous region 1; CH1) and a N-terminal phospho-tyrosine binding domain (PTB). We report her ethe initial characterization of two Shc related human cDNAs: ShcB and ShcC. The ShcB and ShcC cDNAs code for proteins that are highly similar and share the same modular organization as Shc. PTB and SH2 domains of ShcB and ShcC have similar binding specificities in vitro and bind to activated EGFR in a phosphotyrosine-dependent manner. Based on these findings we propose to rename Shc as ShcA. Anti-ShcB and anti-ShcC antibodies recognize specific polypeptides of 52, 47 kDa (ShcB) and 54 kDa (ShcC) in mammalian cells. Since these two genes are predominantly expressed in specific brain tissues, these Shc family members may be involved in cell type-specific signaling, in the nervous system.
Insights
Researchers identified two new Shc-related proteins, ShcB and ShcC, in human cells. These proteins, similar to ShcA, play a role in cell signaling, particularly in the nervous system.
Area of Science:
- Molecular Biology
- Cell Signaling
- Neuroscience
Background:
- Shc proteins are key mediators in signal transduction pathways, linking activated tyrosine kinases to downstream effectors like Ras.
- Two Shc isoforms (52 and 46 kDa) with conserved SH2, CH1, and PTB domains have been previously identified.
- Shc proteins bind to phosphorylated proteins and the Grb2 adaptor, facilitating signal transmission.
Purpose of the Study:
- To characterize two novel Shc-related human cDNAs, designated ShcB and ShcC.
- To investigate the structural and functional similarities and differences between ShcB, ShcC, and the previously known Shc proteins.
- To explore the potential role of ShcB and ShcC in cell type-specific signaling, particularly within the nervous system.
Main Methods:
- Cloning and characterization of ShcB and ShcC human cDNAs.
- In vitro binding assays to assess the specificity of PTB and SH2 domains.
- Immunoblotting using specific antibodies to detect ShcB and ShcC proteins in mammalian cells.
- Analysis of tissue-specific gene expression patterns.
Main Results:
- ShcB and ShcC cDNAs encode proteins highly similar to Shc, sharing the same modular domain organization (PTB, CH1, SH2).
- The PTB and SH2 domains of ShcB and ShcC exhibit similar binding specificities to Shc and bind to activated epidermal growth factor receptor (EGFR) in a phosphotyrosine-dependent manner.
- Specific antibodies detected ShcB (52, 47 kDa) and ShcC (54 kDa) polypeptides in mammalian cells.
- ShcB and ShcC genes show predominant expression in specific brain tissues.
Conclusions:
- The identification and characterization of ShcB and ShcC expand the Shc protein family.
- ShcB and ShcC proteins possess conserved functional domains and binding properties similar to ShcA.
- The tissue-specific expression of ShcB and ShcC in the brain suggests their involvement in neural cell-specific signaling pathways.
- It is proposed to rename the original Shc protein as ShcA to accommodate the newly identified family members.