Sustained Activation of Glial Cell Epidermal Growth Factor Receptor by Bis(thiosemicarbazonato) Metal Complexes Is Associated with Inhibition of Protein Tyrosine Phosphatase Activity

Sorting of activated epidermal growth factor receptor (EGFR) into intraluminal vesicles (ILVs) within the multivesicular body (MVB) is an essential step during the down-regulation of the receptor. The machinery that drives EGFR sorting attaches to the cytoplasmic face of the endosome and generates vesicles that bud into the endosome lumen, but somehow escapes encapsulation itself. This machinery is termed the ESCRT (endosomal sorting complexes required for transport) pathway, a series of multi-protein complexes and accessory factors first identified in yeast. Here, we review the yeast ESCRT pathway and describe the corresponding components in mammalian cells that sort EGFR. One of these is His domain protein tyrosine phosphatase (HD-PTP/PTPN23), and we review the interactions involving HD-PTP and ESCRTs. Finally, we describe a working model for how this ESCRT pathway might overcome the intrinsic topographical problem of EGFR sorting to the MVB lumen.

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Association of Tyrosine Phosphatase Epsilon with Microtubules Inhibits Phosphatase Activity and Is Regulated by the Epidermal Growth Factor Receptor

Molecular and Cellular Biology ◽

10.1128/mcb.02096-06 ◽

2007 ◽

Vol 27 (20) ◽

pp. 7102-7112 ◽

Cited By ~ 19

Author(s):

Tal Sines ◽

Shira Granot-Attas ◽

Sabrina Weisman-Welcher ◽

Ari Elson

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Phosphatase Activity ◽

Specific Activity ◽

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Epidermal Growth ◽

In Cells

ABSTRACT Protein tyrosine phosphatases (PTPs) are key mediators that link physiological cues with reversible changes in protein structure and function; nevertheless, significant details concerning their regulation in vivo remain unknown. We demonstrate that PTPε associates with microtubules in vivo and is inhibited by them in a noncompetitive manner. Microtubule-associated proteins, which interact strongly with microtubules in vivo, significantly increase binding of PTPε to tubulin in vitro and further reduce phosphatase activity. Conversely, disruption of microtubule structures in cells reduces their association with PTPε, alters the subcellular localization of the phosphatase, and increases its specific activity. Activation of the epidermal growth factor receptor (EGFR) increases the PTPε-microtubule association in a manner dependent upon EGFR-induced phosphorylation of PTPε at Y638 and upon microtubule integrity. These events are transient and occur with rapid kinetics similar to EGFR autophosphorylation, suggesting that activation of the EGFR transiently down-regulates PTPε activity near the receptor by promoting the PTPε-microtubule association. Tubulin also inhibits the tyrosine phosphatase PTP1B but not receptor-type PTPμ or the unrelated alkaline phosphatase. The data suggest that reversible association with microtubules is a novel, physiologically regulated mechanism for regulation of tyrosine phosphatase activity in cells.

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