Inhibition of T Cell Signaling by Mitogen-activated Protein Kinase-targeted Hematopoietic Tyrosine Phosphatase (HePTP)

Abstract

Activation of T lymphocytes to produce cytokines is

The protein tyrosine phosphatase HePTP regulates nuclear translocation of ERK2 and can modulate megakaryocytic differentiation of K562 cells

“…When transiently overexpressed in Jurkat or 293 cells, HePTP is associated with ERK even in the absence of stimulation. 11,12 In our stable K562 cell lines, however, we have not observed constitutive association of HePTP with ERK2, which might be explained by lower expression levels as compared to transient transfections. To further investigate the association of HePTP with ERK2 we therefore used transient transfection of 293 cells (Figure 3b).…”

“…HePTP contains two consensus ERK phosphorylation sites (T45 and S72) adjacent to the KIM motif and Saxena et al 11 recently suggested that phosphorylation of these sites might interfere with the binding of HePTP to its substrates. Therefore we asked if such a mechanism could explain our observation that ectopic expression of wild-type HePTP has no significant effect on the nuclear translocation of ERK2 in PMA-treated K562 cells (see Figure 3a).…”

“…21,22 In addition, HePTP can be phosphorylated within the N-terminus by activated ERKs and it was suggested that phosphorylation of these sites also interferes with the binding of HePTP to its substrates. 11 Therefore it was proposed that HePTP is involved in suppression of basal ERK activity in the absence of ERK activating signals.…”

“…The KIM sequence is required for association with and dephosphorylation of active ERK1/2. [11][12][13]15,20 Within this sequence is a consensus site for phosphorylation by cAMP-dependent protein kinase (PKA). It was recently demonstrated that phosphorylation of this site in PTP-SL and HePTP in response to PKA activation inhibits the interaction of these phosphatases with their substrates and, consequently, results in increased ERK activity.…”

“…More recently, the tyrosine-specific protein phosphatase (PTP) HePTP (also known as LC-PTP) was identified as an ERK1/2 phosphatase. [11][12][13] For example, overexpression of HePTP in Jurkat T cells blocks ERK1/2 activation after engagement of the T cell receptor and overexpression in K562 cells interferes with the activation of ERK1/2 in response to PMA. 11,13,14 In T cells, HePTP also binds and dephosphorylates the MAP-kinase family member p38 while in K562 cells ERK2 is the predominant substrate.…”