T-cell protein tyrosine phosphatase (TC-PTP) is a non-transmembrane enzyme. The noncatalytic domain of TC-PTP is alternatively spliced to generate p45TC, which localizes to the nucleus, and p48TC, which contains a hydrophobic C-terminal tail and localizes to the ER. The C-terminal segment of p45TC regulates the activity of the catalytic domain through an intramolecular interaction. The p45TC variant of TC-PTP exits the nucleus upon EGF receptor activation and recognizes the EGF receptor and p52Shc cellular substrates.