Abstract
Protein tyrosine phosphatase MEG2 (PTP-MEG2) is a unique nonreceptor tyrosine phosphatase associated with transport vesicles, where it facilitates membrane trafficking by dephosphorylation of the N-ethylmaleimide-sensitive fusion factor. In this study, we identify the neurotrophin receptor TrkA as a novel cargo whose transport to the cell surface requires PTP-MEG2 activity. In addition, TrkA is also a novel substrate of PTP-MEG2, which dephosphorylates both Tyr-490 and Tyr-674/Tyr-675 of TrkA. As a result, overexpression of PTP-MEG2 down-regulates NGF/TrkA signaling and blocks neurite outgrowth and differentiation in PC12 cells and cortical neurons.
Highlights
PTP-MEG2 is a 68-kDa nonreceptor protein tyrosine phosphatase (PTP)3 that was originally isolated from megakaryocytes but was shown to be expressed in many tissues and cell types, including the brain, leukocytes, and endocrine and exocrine cells [1, 2]
PTP-MEG2 Accumulates at Neurite Termini in PC12 Cells and Cortical Neurons—Endogenous PTP-MEG2 was expressed at relatively low levels in PC12 cells and cortical neurons, as evidenced by immunoblot analysis (Fig. 1, A and B), and, strikingly, exhibited strong accumulation at the neurite terminal inside the growth cone marked by actin staining, as shown by confocal immunofluorescence microscopy (Fig. 1C)
We have identified TrkA as a novel substrate for the nonreceptor protein tyrosine phosphatase PTP-MEG2, which dephosphorylates TrkA at both the kinase activation domain (Tyr-674/675) and the signaling effector binding site (Tyr-490) (Fig. 9)
Summary
PTP-MEG2 is a 68-kDa nonreceptor protein tyrosine phosphatase (PTP)3 that was originally isolated from megakaryocytes but was shown to be expressed in many tissues and cell types, including the brain, leukocytes, and endocrine and exocrine cells [1, 2]. Overexpression of PTP-MEG2 down-regulates NGF/TrkA signaling and blocks neurite outgrowth and differentiation in PC12 cells and cortical neurons. Our data show that PTP-MEG2 facilitates TrkA transport to the cell surface and, importantly, down-regulates NGF/TrkA signal transduction by dephosphorylation of TrkA and reduces neurite outgrowth.
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