Limits...
A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase.

Blanco-Aparicio C, Torres J, Pulido R - J. Cell Biol. (1999)

Bottom Line: The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue, located within the KIM.Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Citológicas, 46010 Valencia, Spain.

ABSTRACT
Protein tyrosine phosphatase PTP-SL retains mitogen-activated protein (MAP) kinases in the cytoplasm in an inactive form by association through a kinase interaction motif (KIM) and tyrosine dephosphorylation. The related tyrosine phosphatases PTP-SL and STEP were phosphorylated by the cAMP-dependent protein kinase A (PKA). The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue, located within the KIM. Upon phosphorylation of Ser(231), PTP-SL binding and tyrosine dephosphorylation of the MAP kinases extracellular signal-regulated kinase (ERK)1/2 and p38alpha were impaired. Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant. These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

Show MeSH
Model of MAP kinase regulation by PKA and PTP-SL. Pools of MAP kinases are maintained in the cytoplasm and into the nucleus by the balance between activation stimuli and the PTP-SL (or other KIM-containing PTPs) inhibitory effects. Upon PKA activation, the association of PTP-SL with the MAP kinase is impaired, and MAP kinase tyrosine phosphorylation and nuclear translocation is favored. The putative regulatory role for serine/threonine phosphatases (PP) in the dephosphorylation of PTP-SL, is indicated (see details in the text).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2168101&req=5

Figure 5: Model of MAP kinase regulation by PKA and PTP-SL. Pools of MAP kinases are maintained in the cytoplasm and into the nucleus by the balance between activation stimuli and the PTP-SL (or other KIM-containing PTPs) inhibitory effects. Upon PKA activation, the association of PTP-SL with the MAP kinase is impaired, and MAP kinase tyrosine phosphorylation and nuclear translocation is favored. The putative regulatory role for serine/threonine phosphatases (PP) in the dephosphorylation of PTP-SL, is indicated (see details in the text).

Mentions: PKA modulates the activity of MAP kinases in a cell type– and stimulus-specific manner by interfering with upstream events from signaling cascades activated through distinct Ras-like GTPases, including Ras, Rap1, and RalGDS (Vossler et al. 1997; Miller et al. 1998). In addition, PKA activity favors the nuclear translocation of ERK1/2 in PC12 and hippocampal neurons, as well as in presynaptic sensory neurons from Aplysia (Impey et al. 1998; Martin et al. 1998; Yao et al. 1998). Our results, showing a crosstalk between the PKA and ERK1/2 and p38α kinases through the tyrosine phosphatase PTP-SL, support the existence of a novel mechanism by which PKA can regulate the activity of the MAP kinases and their translocation to the nucleus (Fig. 5). Such a mechanism would involve the existence, in certain cell types, of a pool of inactive MAP kinases outside of the nucleus, which would be complexed with PTP-SL or other KIM-containing PTPs, including STEP and HePTP (see below). The dissociation equilibrium of the complex would depend upon the cell type– and the stimulus-specific conditions of PKA activity, and the lack of association would be favored by the PKA-mediated phosphorylation of the KIM regulatory residue on the PTP. Thus, upon conditions of PKA activation, both the tyrosine phosphorylation and the entry into the nucleus of the MAP kinases would be prevalent. It should be noted that the expression of PTP-SL and related isoforms is restricted to specialized areas of the brain, including the Purkinje cells in the postnatal cerebellum (Watanabe et al. 1998; van den Maagdenberg et al. 1999), suggesting the possibility of a differential regulation of MAP kinase functions by PTP-SL and PKA during brain development.


A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase.

Blanco-Aparicio C, Torres J, Pulido R - J. Cell Biol. (1999)

Model of MAP kinase regulation by PKA and PTP-SL. Pools of MAP kinases are maintained in the cytoplasm and into the nucleus by the balance between activation stimuli and the PTP-SL (or other KIM-containing PTPs) inhibitory effects. Upon PKA activation, the association of PTP-SL with the MAP kinase is impaired, and MAP kinase tyrosine phosphorylation and nuclear translocation is favored. The putative regulatory role for serine/threonine phosphatases (PP) in the dephosphorylation of PTP-SL, is indicated (see details in the text).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2168101&req=5

Figure 5: Model of MAP kinase regulation by PKA and PTP-SL. Pools of MAP kinases are maintained in the cytoplasm and into the nucleus by the balance between activation stimuli and the PTP-SL (or other KIM-containing PTPs) inhibitory effects. Upon PKA activation, the association of PTP-SL with the MAP kinase is impaired, and MAP kinase tyrosine phosphorylation and nuclear translocation is favored. The putative regulatory role for serine/threonine phosphatases (PP) in the dephosphorylation of PTP-SL, is indicated (see details in the text).
Mentions: PKA modulates the activity of MAP kinases in a cell type– and stimulus-specific manner by interfering with upstream events from signaling cascades activated through distinct Ras-like GTPases, including Ras, Rap1, and RalGDS (Vossler et al. 1997; Miller et al. 1998). In addition, PKA activity favors the nuclear translocation of ERK1/2 in PC12 and hippocampal neurons, as well as in presynaptic sensory neurons from Aplysia (Impey et al. 1998; Martin et al. 1998; Yao et al. 1998). Our results, showing a crosstalk between the PKA and ERK1/2 and p38α kinases through the tyrosine phosphatase PTP-SL, support the existence of a novel mechanism by which PKA can regulate the activity of the MAP kinases and their translocation to the nucleus (Fig. 5). Such a mechanism would involve the existence, in certain cell types, of a pool of inactive MAP kinases outside of the nucleus, which would be complexed with PTP-SL or other KIM-containing PTPs, including STEP and HePTP (see below). The dissociation equilibrium of the complex would depend upon the cell type– and the stimulus-specific conditions of PKA activity, and the lack of association would be favored by the PKA-mediated phosphorylation of the KIM regulatory residue on the PTP. Thus, upon conditions of PKA activation, both the tyrosine phosphorylation and the entry into the nucleus of the MAP kinases would be prevalent. It should be noted that the expression of PTP-SL and related isoforms is restricted to specialized areas of the brain, including the Purkinje cells in the postnatal cerebellum (Watanabe et al. 1998; van den Maagdenberg et al. 1999), suggesting the possibility of a differential regulation of MAP kinase functions by PTP-SL and PKA during brain development.

Bottom Line: The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue, located within the KIM.Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Citológicas, 46010 Valencia, Spain.

ABSTRACT
Protein tyrosine phosphatase PTP-SL retains mitogen-activated protein (MAP) kinases in the cytoplasm in an inactive form by association through a kinase interaction motif (KIM) and tyrosine dephosphorylation. The related tyrosine phosphatases PTP-SL and STEP were phosphorylated by the cAMP-dependent protein kinase A (PKA). The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue, located within the KIM. Upon phosphorylation of Ser(231), PTP-SL binding and tyrosine dephosphorylation of the MAP kinases extracellular signal-regulated kinase (ERK)1/2 and p38alpha were impaired. Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant. These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

Show MeSH