Degradation of the Met Tyrosine Kinase Receptor by the Ubiquitin-Proteasome Pathway

Jeffers, Michael; Taylor, Gregory A.; Weidner, K. Michael; Ōmura, Satoshi; Woude, George F. Vande

doi:10.1128/mcb.17.2.799

Cited by 214 publications

(199 citation statements)

References 51 publications

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“…This process has been observed in various cell types and has been induced with different agents such as PMA, suramine, epidermal growth factor (EGF), lysophosphatidic acid (LPA), and HGF/SF (Prat et al, 1991;Galvani et al, 1995;Nath et al, 2001;Wajih et al, 2002). In addition, other fragments have been observed, such as phosphorylated membrane-anchored fragments degraded via the proteosomal pathway or labile nuclear fragments (Jeffers et al, 1997;Pozner-Moulis et al, 2006). Our work suggests that these previously observed fragments of Met, initially described independently, could be produced through a common proteolytic process, PS-RIP.…”

Section: Discussionmentioning

confidence: 99%

“…Many other fragments of Met have been described, but their biological functions, and the mechanisms involved in their generation have not been investigated. Examples include an extracellular fragment of Met, released upon ectodomain shedding into the culture supernatant (Prat et al, 1991;Galvani et al, 1995;Wajih et al, 2002), and a labile 55-kDa intracellular fragment of Met produced in epithelial cells (Jeffers et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Foveau

Ancot

Leroy

et al. 2009

MBoC

113

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Foveau

Ancot

Leroy

et al. 2009

MBoC

113

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“…Stimulation of the Met receptor with HGF/SF induces tyrosine phosphorylation of the receptor, and stimulation with high levels of HGF/SF leads to detectable Met receptor ubiquitination and enhanced degradation (Jeffers et al, 1997b;Kamei et al, 1999;Shen et al, 2000;Abella et al, 2005). The juxtamembrane region of Met contains an additional docking site, Y1003, which acts as a negative regulator of Met biological activity , and that is absent in the Tpr-Met oncogene (Figure 1).…”

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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“…Notably, abnormal activation of MET is responsible for resistance to targeted therapies against the vascular endothelial growth factor receptor (VEGFR) in GBM and inhibitors of the epidermal growth factor receptor (EGFR) in lung cancers (4)(5)(6). Although it is well known that upon the binding to HGF, MET is phosphorylated and activated on the plasma membrane, leading to the activation of downstream targets such as PI3K, AKT and MAPK/ERKs (7,8), the mechanism by which HGF and MET regulate the invasive cell growth and cell motility, however, remains less clear.…”

mentioning

confidence: 99%

HGF-induced formation of the MET–AXL–ELMO2–DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion

Xiong

Abdalla

et al. 2018

Journal of Biological Chemistry

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The MET proto-oncogene encoded receptor tyrosine kinase MET and AXL receptor tyrosine kinase (AXL) are independently operating receptor tyrosine kinases (RTKs) that are functionally associated with aggressive and invasive cancer cell growth. However, how MET and AXL regulate the migratory properties of cancer cells remains largely unclear. We report here that addition of hepatocyte growth factor (HGF), the natural ligand of MET, to serum-starved human glioblastoma cells induces the rapid activation of both MET and AXL and formation of highly polarized MET-AXL clusters on the plasma membrane. HGF also promoted the formation of the MET and AXL protein complexes and phosphorylation of AXL, independently of the AXL's ligand, growth arrest-specific 6 (GAS6). The HGF-induced MET-AXL complex stimulated the rapid and dynamic cytoskeleton reorganization by activating the small GTPase RAC1, a process requiring both MET and AXL kinase activities. We further found that HGF also promotes the recruitment of ELMO2 and DOCK180, a bipartite guanine nucleotide exchange factor for RAC1, to the MET-AXL complex and thereby stimulates the RAC1-dependent cytoskeleton reorganization. We also demonstrated that the MET-AXL-ELMO2-DOCK180 complex is critical for HGF-induced cell migration and invasion in glioblastoma or other cancer cells. Our findings uncover a critical HGF-dependent signaling pathway that involves the assembly of a large protein complex consisting of MET, AXL, ELMO2, and DOCK180 on the plasma membrane, leading to RAC1-dependent cell migration and invasion in various cancer cells. __________________________________The MET oncogene was originally identified as the oncogenic TPR-MET fusion gene due to a chromosomal translocation fusion event in an osteosarcoma cell line (1,2). The TPR-MET fusion protein exhibits a constitutively active MET tyrosine kinase (RTK) that is normally expressed in cells of epithelial origins during embryonic development for mitogenesis and morphogenesis of various tissues (1,2). In embryogenesis or wound healing process in adult tissues, activation of the MET RTK by its cognate ligand, hepatocyte growth factor (HGF, also called scatter factor), initiates a morphogenic program of "invasive growth" that promotes disruption and remodeling of intercellular contacts, accompanied by cell proliferation, cell migration and invasion (1,2). The MET-dependent invasive growth signals are also present in many highly aggressive cancer cells. The abnormalities of MET in human malignancies are frequent and widely observed (1,2). In glioblastoma multiforme (GBM), a highly aggressive brain tumor, the level of MET is often aberrantly up-regulated (3). Notably, abnormal activation of MET is responsible for resistance to targeted therapies against the vascular endothelial growth factor receptor (VEGFR) in GBM and inhibitors of the epidermal growth factor receptor (EGFR) in lung cancers (4-6). Although it is well known that upon the binding to HGF, MET is phosphorylated and activated on the plasma membrane, ...

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Degradation of the Met Tyrosine Kinase Receptor by the Ubiquitin-Proteasome Pathway

Cited by 214 publications

References 51 publications

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

From Tpr-Met to Met, tumorigenesis and tubes

HGF-induced formation of the MET–AXL–ELMO2–DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion

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