p66Shc–the protein with many functions

The role of ShcA proteins in oncogenic processes has been intensively studied in many models, and their functions in tumors of the nervous system have gained much attention. The ShcA transcript has three isoforms, p46Shc, p52Shc, and p66Shc, which have similar structures and adaptor functions. Classically, all ShcA proteins that are located in the cytoplasm and ER are involved in growth factor signaling as they become tyrosine phosphorylated in response to growth factors binding to tyrosine receptor-associated kinases at the plasma membrane. The signal is transmitted by the ShcA complex with Grb2, thus recruits the Son of sevenless (Sos) protein, exchanging GDP for GTP in the Ras protein, which leads to its activation. Shorter ShcA isoforms (p46Shc and p52Shc) facilitate Ras activation after Grb2-Sos complex formation and binding. p66Shc, the longest isoform of the Shc adaptor protein 1 subfamily, possesses an amino-terminal extension and collagen homology domain 2 (CH2), which, when phosphorylated, prevents Grb2 and Sos complex formation and therefore Ras activation. The CH2 domain of p66Shc also contains a serine phosphorylation site that undergoes phosphorylation in response to oxidative stimuli. The pro-oxidant p66Shc-associated pathway has been described as an important factor contributing to multiple pathologies by increasing oxidative stress and damage in diabetes, cardiovascular disorders, neurodegeneration, and mitochondrial disorders. p66Shc is also an important determinant of mammalian aging and is involved in cancer development and progression.

Together with my team we want to answer the questions:

1) Is the p66Shc protein involved in the cellular response to the oxidative stress?

2) Does the level of p66Shc depend on the cancer type?

3) How p66Shc protein is involved in cellular metabolism regulation?