Figure 1
Schematic representation of the structural modularity of the Shc family of proteins. Shc proteins share the same structural hallmarks of highly conserved PTB and SH2 domains and poorly conserved CH2 and CH1 domains. Three conserved tyrosine phosphorylation sites exist in the CH1 domain (yellow). In ShcC and ShcD/RaLP, additional tyrosine phosphorylation residues (non-conserved) are present in the same CH1 domain (green). SER36 in the p66ShcA-CH2 domain is responsible for the oxidative-stress response function. RaLP-CH2 also contains a putative serine site for phosphorylation. A cysteine (C) residue in the p66ShcA-CH2 domain of ShcB and ShcD/RaLP (blue) is involved in oligomerization. A cytochrome c (CB) binding site is present only in p66ShcA but not in other Shc proteins (pink). An Adaptin binding motif (A) is present in all Shc proteins except ShcD/RaLP (cream-coloured) (adapted from Melanie and Jones, 2012).
Figure 2
Shc acts as a bridge connecting the extracellular signal and the different intracellular signalling pathways. Shc is recruited by activated cell surface receptors or integrins. Shc can then be phosphorylated either by receptor tyrosine kinases (EGFR) or cytosolic tyrosine kinases (Fyn, a protein of the Src family). Phosphorylated Shc can then interact with Grb2, leading to the activation of different pathways such as MAPK, PI3K/Akt and RhoA via the activation of Ras. Therefore, Shc proteins trigger different intracellular cascades, resulting in various cellular responses (adapted from Zhu and Parada, 2002).
Figure 3
p66ShcA has a key role in the oxidative stress response. p66ShcA is phosphorylated on Ser36 via the activation of stress kinases such as JNK after the exposure of cells to oxidative stress agents (e.g., H2O2 and UV). This results in translocation of a fraction of p66ShcA into the mitochondrial intermembrane space, where it binds physically with cytochrome c (Cyto-c), which results in a mitochondrial permeability transition (MPT). The release of cytochrome c results in apoptosome formation, initiating the apoptotic process. p66ShcA mediates the transcription factor FOX phosphorylation, which results in an inhibition in the transcription of scavenging enzymes such as catalase and MnSOD. Upon VEGF stimulation in endothelial cells, p66ShcA is phosphorylated at Ser54 and Thr286 in response to Rac1 activation. Consequentially, the produced intracellular reactive oxygen species (ROS) initiate the VEGF-mediated angiogenic response.
Figure 4
Schematic representation illustrating the phosphorylation sites on p66ShcA. There are three tyrosine phosphorylation sites and a threonine phosphorylation residue in the CH1 domain. There is one serine phosphorylation site on (Serine 138) the PTB domain as well as two serine phosphorylation sites in the amino terminal CH2 domain. p66ShcA has a unique cytochrome c binding region (CB). Ser36, Ser59, Ser138 and Thr386 are involved in the oxidative stress response, whereas S154 has a role in the directional movement of pancreatic cells. The phosphorylation of tyrosine residues in the CH1 domain are involved in MAPK activation (Adapted from Rajendran et al. 2010).
| Akt | Protein kinase B |
| ALK | Anaplastic lymphoma kinase |
| AP2 complex | Assembly protein complex2 |
| BDNF | Brain derived neurotrophic factor |
| CH | Collagen homology domain |
| C-terminus | Carboxy-terminus |
| EGF | Epidermal growth factor |
| EGFR | Epidermal growth factor receptor |
| ErBb2 | Human epidermal growth factor receptor 2 (HER2/neu) |
| ERK | Extracellular signal-regulated kinase |
| FAK | Focal adhesion kinase |
| Gab1 | Grb2-associated binding protein |
| Grb2 | Growth factor receptor-bound protein2 |
| H2O2 | Hydrogen peroxide |
| IGF | Insulin growth factor |
| IGF1R | Insulin-like growth factor 1 receptor |
| IQGAP1 | Ras GTPase-activating-like protein |
| IRS | Insulin receptor substrate |
| JNK | C-Jun N-terminal kinases |
| MAPK | Mitogen- activated kinase pathway |
| MEK | MAP/ERK kinase |
| Met | Mesenchymal-epithelial transition factor (HGF receptor) |
| MIF | Macrophage migration inhibitory factor |
| Mpl | Myeloproliferative leukaemia protein |
| NAD | Nicotinamide adenine dinucleotide |
| NADH | NAD+ hydrogen (H) |
| NCAM | Neural cell adhesion molecule |
| Nedd8 | Neural precursor cell expressed developmentally down-regulated protein 8 |
| N-terminal | Amino-terminal |
| PI3K | Phosphoinositide 3-kinase |
| PKC | Protein kinase C |
| PLCγ | Phospholipase C gamma |
| PC-PLC | Phosphatidylcholine-Selective phospholipase |
| PTB | Phosphorylated binding domain |
| PTEN | Phosphatase and tensin homolog |
| PTP-PEST | Protein tyrosine phosphatase contains PEST |
| RaLP | Rai-like protein |
| Ran | Ras-related nuclear protein |
| Ret | Rearranged during transfection |
| ROS | Reactive oxygen species |
| RTK | Receptor tyrosine kinase |
| Ser/S | Serine |
| SH2 | Src homology 2 |
| Shc | Src homology and collagen |
| SHIP | SH2 domain containing inositol 5-phosphatase |
| Sos | Son of sevenless |
| Src | Proto-oncogene tyrosine-protein kinase Src |
| TGF-β | Transforming growth factor-beta |
| Trk | Nerve growth factor receptor |
| Tyr/Y | Tyrosine |
| UV | Ultra-Violet light |
| VEGF | Vascular endothelial growth factor |