Defective downregulation of receptor tyrosine kinases in cancer

Bache, Kristi G.; Slagsvold, Thomas; Stenmark, Harald

doi:10.1038/sj.emboj.7600292

Cited by 183 publications

(164 citation statements)

References 45 publications

(75 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: 69%

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: 69%

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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show abstract

“…Hence, the role of these proteins in vesicular trafficking could be key to their tumor suppressing activity. As the study of dysregulated protein transport is becoming a major theme in cancer research (Bache et al, 2004;Polo et al, 2004), elucidating how the tumor suppressor merlin controls protein transport constitutes an essential contribution in this emerging field.…”

Section: Discussionmentioning

confidence: 99%

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

et al. 2008

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The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cellto-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and plateletderived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.

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“…Increasing number of reports support that loss of negative regulation leads to deregulation of many RTKs and other receptors in human cancer (Peschard and Park, 2003;Bache et al, 2004). Naturally occurring somatic mutants of the Met receptor, which lead to loss of the Cbl TKB-binding site, have been identified in human lung cancers and, as a consequence, these receptors are poorly ubiquitinated and not targeted for degradation (Kong-Beltran et al, 2006) (Figure 3).…”

Section: Loss Of Cbl Ubiquitylation In Oncogenic Rtksmentioning

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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Defective downregulation of receptor tyrosine kinases in cancer

Cited by 183 publications

References 45 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

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

From Tpr-Met to Met, tumorigenesis and tubes

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