Protein-tyrosine Phosphatase 1B Modulates Early Endosome Fusion and Trafficking of Met and Epidermal Growth Factor Receptors

Sangwan, Veena; Abella, Jasmine V.; Lai, Andrea; Bertos, Nicholas; Stuible, Matthew; Tremblay, Michel L.; Park, Morag

doi:10.1074/jbc.m111.270934

Cited by 28 publications

(23 citation statements)

References 54 publications

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“…This initial rephosphorylation is then enhanced and prolonged likely by the reduced expression of a critical MET-negative regulator, the phosphatase PTP1B (19). Loss of PTP1B not only increases MET phosphorylation and signaling, but it also dampens receptor trafficking to the early endosomal compartment (19,26); thus, the observed reduction in PTP1B levels could also account for the delayed kinetics of receptor endocytosis following inhibitor withdrawal. Even if the active receptor is primarily present at the cell surface during drug washout, a small fraction of phospho-MET can be detected on early endosomes.…”

Section: Discussionmentioning

confidence: 99%

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Rebound Effects Caused by Withdrawal of MET Kinase Inhibitor Are Quenched by a MET Therapeutic Antibody

et al. 2016

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MET oncogene amplification is emerging as a major mechanism of acquired resistance to EGFR-directed therapy in lung and colorectal cancers. Furthermore, MET amplification predicts responsiveness to MET inhibitors currently in clinical trials. Among the anti-MET drugs available, ATP-competitive small-molecule kinase inhibitors abrogate receptor autophosphorylation and downstream activation of ERK1/2 and AKT, resulting in cell-cycle arrest. However, this antiproliferative effect allows persistence of a pool of cancer cells that are quiescent but alive. Once the inhibition is removed, rebound activation of MET-driven cell proliferative pathways and tumor growth may occur, an adverse event observed frequently in clinical settings after drug discontinuation. Here we show that inhibitor withdrawal prompts receptor phosphorylation to levels higher than those displayed at steadystate and generates a rebound effect pushing quiescent cancer cells back into the cell cycle, both in vitro and in experimental tumor models in vivo. Mechanistically, we found that inhibitor treatment blocks MET endocytosis, causing a local increase in the number of receptors at the plasma membrane. Upon inhibitor washout, the receptor is readily rephosphorylated. The initial phosphorylation is not only increased but also prolonged in duration due to downmodulation of a phosphatase-mediated MET-negative feedback loop, which accompanies receptor internalization. Notably, treatment with a MET therapeutic antibody that induces proteolytic cleavage of the receptor at the cell surface substantially prevents this rebound effect, providing a rationale to combine or alternate these mechanistically different types of MET-targeted therapy.

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Section: Discussionmentioning

confidence: 99%

“…Of these, one did not receive any further administration (without JNJ-605, n ¼ 6) while the other (without JNJ-605 with MvDN30PEG, n ¼ 5) was treated with MvDN30-PEG (15 mg/kg; ref. 12) every three days (day 23,26,29). At day 29, mice were injected intraperitoneally with 75 mg/mouse of EdU in 200 mL of PBS.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Rebound Effects Caused by Withdrawal of MET Kinase Inhibitor Are Quenched by a MET Therapeutic Antibody

et al. 2016

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“…First, ER-based ubiquitination and degradation mechanisms can regulate the levels of nascent RTKs eventually targeted to the plasma membrane, as recently shown for ErbB3 levels controlled by the E3 ubiquitin ligase Nrdp1 at the ER (Fry et al 2011). Second, ER-localized protein tyrosine phosphatase PTP1B plays multiple roles in inactivating ligand-bound RTKs after internalization and in modulating their endocytic trafficking (Stuible and Tremblay 2010;Sangwan et al 2011). A recent identification of direct contact sites between endosomes and ER provides a conceptual framework of how an ER-tethered enzyme can affect the function of RTKs on the endosomal membranes (Fig.…”

Section: The Role Of Endoplasmic Reticulum In Modulating Rtk Signalingmentioning

confidence: 99%

Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

Miączyńska

2013

Cold Spring Harbor Perspectives in Biology

111

100

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The intracellular trafficking machinery contributes to the spatial and temporal control of signaling by receptor tyrosine kinases (RTKs). The primary role in this process is played by endocytic trafficking, which regulates the localization of RTKs and their downstream effectors, as well as the duration and the extent of their activity. The key regulatory points along the endocytic pathway are internalization of RTKs from the plasma membrane, their sorting to degradation or recycling, and their residence in various endosomal compartments. Here I will review factors and mechanisms that modulate RTK signaling by (1) affecting receptor internalization, (2) regulating the balance between degradation and recycling of RTK, and (3) compartmentalization of signals in endosomes and other organelles. Cumulatively, these mechanisms illustrate a multilayered control of RTK signaling exerted by the trafficking machinery.

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“…EGFR dephosphorylation is a physiologically important means of terminating recep-tor signaling, and inhibition of EGFR phosphatases results in EGFR phospho-activation (26). We next investigated the role of PTP1B, a well-characterized tyrosyl-directed EGFR phosphatase (27,28), in PRL-3-induced EGFR hyperactivation. Immunoblot analysis revealed a decrease in PTP1B protein expression in A431-PRL-3 cells compared with A431-vec cells, concomitant with an increase in phosphorylated EGFR ( Figure 3A).…”

Section: Prl-3-mediated Hyperactivation Of Egfr Is Partially Dependenmentioning

confidence: 99%

Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

et al. 2013

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Metastasis-associated phosphatase of regenerating liver-3 (PRL-3) has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3-induced hyperactivation of EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3-induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3-induced hyperactivation of EGFR correlated with increased cell growth, promigratory characteristics, and tumorigenicity. Moreover, PRL-3 induced cellular addiction to EGFR signaling, as evidenced by the pronounced reversion of these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab. The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3-driven cancer progression. We propose that elevated PRL-3 expression is an important clinical predictive biomarker for favorable anti-EGFR cancer therapy.

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Protein-tyrosine Phosphatase 1B Modulates Early Endosome Fusion and Trafficking of Met and Epidermal Growth Factor Receptors

Cited by 28 publications

References 54 publications

Rebound Effects Caused by Withdrawal of MET Kinase Inhibitor Are Quenched by a MET Therapeutic Antibody

Rebound Effects Caused by Withdrawal of MET Kinase Inhibitor Are Quenched by a MET Therapeutic Antibody

Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

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