Met Receptor Dynamics and Signalling

Hammond, Dean E.; Carter, S.; Clague, Michael J.

doi:10.1007/978-3-540-69494-6_2

Cited by 27 publications

(36 citation statements)

References 103 publications

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“…␣-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors also require ubiquitination and proteasomal degradation of the scaffolding protein PSD-95 in order to undergo endocytosis (28). Our previous findings that Met degradation requires both correct endosomal sorting and proteasome activity have also been proposed to reflect a requirement for degradation of an accessory factor (6).…”

Section: Lys 48 -Linked Ubiquitin Enhances Met Receptor Degradation Umentioning

confidence: 99%

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The Met Receptor Degradation Pathway

Carter¹,

Urbé²,

Clague

2004

Journal of Biological Chemistry

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Acute stimulation of the receptor for the hepatocyte growth factor/scatter factor Met leads to receptor ubiquitination and down-regulation through the lysosomal degradation pathway. We have determined that the Met receptor undergoes multiple monoubiquitination as opposed to the appendage of polyubiquitin chains. Nevertheless, overexpression of ubiquitin in HEK293T cells enhances the rate of Met receptor degradation, in contrast to a point mutant of ubiquitin (K48R) that cannot form Lys 48 -linked polyubiquitin chains. Furthermore, an enhancement of Met degradation is also seen under conditions where the proteasome is inhibited by lactacystin. We propose that this reflects polyubiquitin-dependent sorting of Met, as the overexpression of ubiquitin but not K48R ubiquitin also restores hepatocyte growth factor-dependent phosphorylation of the endosomal coat protein Hrs from inhibition by lactacystin. Our data indicate a requirement for K48-R-linked polyubiquitin for Met endosomal trafficking independent of its canonical function of targeting for proteasomal degradation.

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Section: Lys 48 -Linked Ubiquitin Enhances Met Receptor Degradation Umentioning

confidence: 99%

“…Previous studies have shown that acute HGF stimulation leads to down-regulation of the receptor (6). This degradation pathway accompanies receptor endocytosis and is sensitive to the proton pump inhibitor bafilomycin (7), which indirectly inhibits acid-dependent lysosomal proteases.…”

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confidence: 99%

The Met Receptor Degradation Pathway

Carter¹,

Urbé²,

Clague

2004

Journal of Biological Chemistry

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“…Enhancement-HGF binding to its plasma membrane receptor tyrosine kinase, c-Met, induces a variety of cell functions (7,8,42), including EC barrier enhancement (5). However, the mechanism by which this occurs remains poorly defined.…”

Section: Role Of Cd44 In Hgf/c-met-mediated Human Ec Barriermentioning

confidence: 99%

“…The HGF receptor tyrosine kinase, c-Met, is a disulfidelinked ␣␤-heterodimer that has been identified previously as a proto-oncogene (6,7). The 170-kDa c-Met precursor is glycosylated and then cleaved into a 50-kDa extracellular ␣-chain and a 140-kDa membrane-spanning ␤-chain.…”

mentioning

confidence: 99%

“…The 170-kDa c-Met precursor is glycosylated and then cleaved into a 50-kDa extracellular ␣-chain and a 140-kDa membrane-spanning ␤-chain. The c-Met protein serves as the high affinity receptor for its natural ligand, HGF (also called scatter factor), a paracrine factor produced by stromal and mesenchymal cells, acting on c-Met-expressing cells, including EC (7,8). Activation of the HGF/c-Met signaling pathway, which requires phosphorylation of various specific tyrosine residues on c-Met itself, leads to cellular responses, including increased proliferation, scattering (cellcell repulsion), increased motility, invasion, and branching morphogenesis (7,8).…”

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confidence: 99%

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CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

Singleton

Salgia

Moreno‐Vinasco

et al. 2007

Journal of Biological Chemistry

108

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The preservation of vascular endothelial cell (EC) barrier integrity is critical to normal vessel homeostasis, with barrier dysfunction being a feature of inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury. Therefore, agents that preserve or restore vascular integrity have important therapeutic implications. In this study, we explored the regulation of hepatocyte growth factor (HGF)-mediated enhancement of EC barrier function via CD44 isoforms. We observed that HGF promoted c-Met association with CD44v10 and recruitment of c-Met into caveolin-enriched microdomains (CEM) containing CD44s (standard form). Treatment of EC with CD44v10-blocking antibodies inhibited HGF-mediated c-Met phosphorylation and c-Met recruitment to CEM. Silencing CD44 expression (small interfering RNA) attenuated HGF-induced recruitment of c-Met, Tiam1 (a Rac1 exchange factor), cortactin (an actin cytoskeletal regulator), and dynamin 2 (a vesicular regulator) to CEM as well as HGF-induced trans-EC electrical resistance. In addition, silencing Tiam1 or dynamin 2 reduced HGF-induced Rac1 activation, cortactin recruitment to CEM, and EC barrier regulation. We observed that both HGF-and high molecular weight hyaluronan (CD44 ligand)-mediated protection from lipopolysaccharide-induced pulmonary vascular hyperpermeability was significantly reduced in CD44 knock-out mice, thus validating these in vitro findings in an in vivo murine model of inflammatory lung injury. Taken together, these results suggest that CD44 is an important regulator of HGF/c-Met-mediated in vitro and in vivo barrier enhancement, a process with essential involvement of Tiam1, Rac1, dynamin 2, and cortactin.

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Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

Bogatkevich¹,

Ludwicka-Bradley²,

Highland³

et al. 2007

Arthritis & Rheumatism

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Objective. To compare the composition of cytokines in African American and Caucasian patients with systemic sclerosis (SSc; scleroderma) and in healthy individuals, particularly the expression and function of hepatocyte growth factor (HGF).Methods. Bronchoalveolar lavage (BAL) fluid samples were analyzed using cytokine array techniques. HGF in plasma and cell culture medium samples was measured by enzyme-linked immunosorbent assay. Connective tissue growth factor (CTGF), type I collagen expression, and c-Met receptor phosphorylation were studied by immunoblotting.Results Conclusion. Ethnic differences exist in terms of antifibrotic HGF expression in lung fibroblasts derived from Caucasian and African American subjects. Reduced levels of HGF as well as a deficiency in c-Met receptor function appear to be present in African American patients with SSc. These findings may explain in part the greater disease severity and worse prognosis observed in African Americans with SSc.

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Met Receptor Dynamics and Signalling

Cited by 27 publications

References 103 publications

The Met Receptor Degradation Pathway

The Met Receptor Degradation Pathway

CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

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