Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases

Marmor, Mina D.; Yarden, Yosef

doi:10.1038/sj.onc.1207390

Cited by 352 publications

(337 citation statements)

References 151 publications

(145 reference statements)

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“…Overexpression and impaired downregulation of the EGFR play an important role in cancer development (44,45); and cancer therapy can induce its downregulation through induction of ubiquitination or activation of caspases (46)(47)(48). Our findings suggest downregulation of the EGFR as a novel mechanism of action for HNK.…”

Section: Discussionmentioning

confidence: 87%

Honokiol, a natural biphenyl, inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest

Wolf¹,

O’Kelly

Wakimoto

et al. 2007

Int J Oncol

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Abstract. Honokiol (HNK), a naturally occurring biphenyl, possesses potent antineoplastic and antiangiogenic properties. We investigated the in vitro and in vivo activity of HNK against breast cancer. HNK exhibited potent anti-proliferative activity against breast cancer cell lines and enhanced the activity of other drugs used for the treatment of breast cancer. In vivo, HNK was highly effective against breast cancer in nude mice. We identified two different effects of HNK on breast cancer cells: cell cycle inhibition, observed at lower doses of HNK, and induction of apoptosis, observed at higher doses of the compound. Our data suggest that HNK is a systemically available, non-toxic inhibitor of breast cancer growth and should be examined for clinical applications.

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Section: Discussionmentioning

confidence: 87%

Honokiol, a natural biphenyl, inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest

Wolf¹,

O’Kelly

Wakimoto

et al. 2007

Int J Oncol

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“…Stabilization of HER2 and HER2 dimers in presence of lapatinib Tyrosine receptor endocytosis and degradation is regulated by post-translational modifications such as receptor phosphorylation and ubiquitination (Marmor and Yarden, 2004). To evaluate the potential role of receptor ubiquitination in lapatinib-induced HER2 accumulation, we transiently expressed hemagglutinin (HA)-tagged ubiquitin in MCF-7HER2 cells and analysed HER2 ubiquitination in presence of lapatinib, trastuzumab or the combination of both.…”

Section: Resultsmentioning

confidence: 99%

“…A key regulator of HER receptor degradation is the E3 ubiquitin ligase c-Cbl (Marmor and Yarden, 2004). Although E3 ubiquitin ligase c-Cbl shows only a marginal effect in ligand-induced HER2 ubiquitination (Wang et al, 1999;Hommelgaard et al, 2004), it does play a role in receptor degradation when c-Cbl is overexpressed or recruited following treatment with anti-HER2 antibodies (Klapper et al, 2000;Wolpoe et al, 2003).…”

Section: Effects Of Lapatinib and Trastuzumab On Bt474 Xenograftsmentioning

confidence: 99%

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

et al. 2008

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Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially nonoverlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo-(HER2/HER2) and hetero-(HER2/EGFR and HER2/HER3) dimers. Lapatinibinduced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

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“…The rapid removal of growth factor receptors from the cell surface, and subsequent targeting to lysosomal degradative compartments, provides a down-regulation mechanism important for preventing sustained activation of signaling pathways, which could potentially lead to cellular transformation (reviewed in Marmor and Yarden, 2004). Receptor downregulation is dependent on RTK activation and ubiquitination (Katzmann et al, 2001;Buchberger, 2002;Davies et al, 2004) by the Cbl family of ubiquitin ligases (Joazeiro et al, 1999;Yokouchi et al, 1999;Keane et al, 1999;Thien and Langdon, 2001).…”

Section: Regulation Of Met Downregulation: Consequence For Oncogenic mentioning

confidence: 99%

From Tpr-Met to Met, tumorigenesis and tubes

2007

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The receptor for hepatocyte growth factor (HGF)/scatter factor (SF), Met, controls a program of invasive epithelial growth through the coordination of cell proliferation and survival, cell migration and epithelial morphogenesis. This process is important during embryogenesis and for organ regeneration in the adult. However, when deregulated the HGF/SF-Met signaling axis contributes to tumorigenesis and metastasis. Studies on the oncogenic activation of the Met receptor have shed light on the molecular mechanisms underlying the oncogenic activation of receptor tyrosine kinase (RTKs). More than a decade ago, work on the Met related oncogene, Tpr-Met, revealed the mechanism for activation of RTK-derived oncogenes generated following chromosomal translocation. More recently, studies on the mechanisms of downregulation of the Met RTK highlight a role for loss of downregulation in RTK oncogenic activation.

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Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases

Cited by 352 publications

References 151 publications

Honokiol, a natural biphenyl, inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest

Honokiol, a natural biphenyl, inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

From Tpr-Met to Met, tumorigenesis and tubes

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