Interaction of the protein tyrosine phosphatase TC PTP with cellular proteins involved in intracellular transport processes

Abstract

Protein tyrosine phosphatases {PTPs) and their associated signaling newlinepathways are crucial for the regulation of numerous cell functions including newlinegrowth, mitogenesis, motility, cell-cell interactions, metabolism, signal newlinetransduction and gene expression. T cell protein tyrosine phosphatase TCPTP newline(encoded by PTPN2 gene) is an intracellular protein tyrosine phosphatase, newlinewhich is ubiquitously expressed. There are two splice variants of TCPTP in newlinehuman cells- TC45 (387 amino acids) and TC48 (415 amino acids), which vary newlineat their C-terminal ends. The last 6 amino acids of TC45 are replaced by 34 newlineamino acids (mostly hydrophobic) in TC48 in human as well as rat proteins. This newlinedifference in the C-terminus determines the differential subcellular localization, newlinesubstrate specificity and enzymatic properties of these two splice variants. newlineTC45 localizes to the nucleus by virtue of a bipartite nuclear localization signal newlinepresent in the C-terminus. This C-terminal region of TC45 is also involved in newlinebinding to DNA. The TC48 isoform is present in the endoplasmic reticulum (ER) newlineand also in the nuclear membrane. The ER localization is determined by two newlinesignal sequences present in the C-terminal 70 amino acids of TC48. newlineSeveral substrates of TC45 have been identified, most of which are newlinecytoplasmic the only exceptions are Stat proteins which are nuclear. However newlineonly EGF receptor in the ER is a specific substrate of TC48 whereas EGF newlinereceptor in the plasma membrane is dephosphorylated by TC45. TC48 as well newlineas TC45 are able to downregulate insulin-induced signaling by newlinedephosphorylating the insulin receptor. Thus no substrates or regulators have newlinebeen identified, which specifically interact with TC48 but not with TC45 isoform. newlineAlthough the sequences which target TC48 to the ER have been identified in the newlineC-terminal 70 amino acid region, these sequences do not have any of the well newlineknown ER targeting signals such as KDEL, dilysine or diarginine motifs.