The hepatocyte growth factor/ met pathway in development, tumorigenesis, and B-cell differentiation

Voort, Robbert van der; Taher, T. E. I.; Derksen, Patrick W.B.; Spaargaren, Marcel; Neut, Ronald van der; Pals, Steven T.

doi:10.1016/s0065-230x(00)79002-6

Cited by 98 publications

(82 citation statements)

References 340 publications

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“…10,11 HGF and its receptor tyrosine kinase Met induce complex biological responses in target cells including growth, survival, and motility. In mice, Met or Hgf deficiency results in embryonic death with severe defects in the development of the placenta, liver, and limb muscles, whereas uncontrolled activation of Met, in both mice and humans, has been implicated in tumor growth, invasion, and metastasis (reviewed by van der Voort et al 13 ) Of note, the finding of Met mutations in hereditary papillary renal carcinoma has established a causative role of Met in human cancer. 33 These mutations result in enhanced kinase activity upon stimulation with HGF and were shown to mediate transformation, invasive growth, and protection from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…All known biological effects of HGF are transduced via the transmembrane tyrosine kinase Met. Whereas a functional HGF/Met pathway is indispensable for mammalian development, uncontrolled activation of Met is oncogenic and has been implicated in growth, invasion, and metastasis of a variety of tumors (reviewed by van der Voort et al 13 ). This uncontrolled Met activation may involve a variety of mechanisms including translocation, mutation, or amplification of the MET gene, and autocrine-or paracrine-Met stimulation.…”

Section: Introductionmentioning

confidence: 99%

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The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

et al. 2003

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The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/ scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para-or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and antiapoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

et al. 2003

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“…[18][19][20][21][22] In addition to these activities, HGF has morphogenic and angiogenic activities, [23][24][25] and is involved in organ regeneration and tumorigenesis. 26,27 HGF, after binding to its specific receptor tyrosine kinase (cMet), induces various biological effects mainly through activation of PI3-K and Akt kinases. [28][29][30][31][32] In this respect, HGF is a prototypical prosurvival growth factor.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

et al. 2003

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Rac1-regulated reactive oxygen species (ROS) production has been implicated in apoptosis. In contrast, pleiotropic protein kinase Akt protects against apoptosis. However, the pro-and antiapoptotic mechanisms of rac1 and Akt, respectively, and the intersection between these mechanisms are incompletely understood. In a model of oxidative stress and apoptosis induced by hypoxia/reoxygenation (H/R) in primary hepatocytes, activation of the PI3-K Akt axis by the prosurvival hepatocyte growth factor (HGF) inhibited H/Rstimulated rac1 activation and intracellular ROS production, and suppressed apoptosis. Suppression of PI3-K or Akt activity abrogated the inhibitory effect of HGF on rac1 activity and rac1-regulated oxidative stress. Furthermore, constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1, inhibit rac1 activation, and suppress rac1-regulated ROS production. These findings demonstrate that growth factor-stimulated activation of PI3-K-Akt is necessary and sufficient to suppress intracellular oxidative stress and apoptosis by inhibiting activation of proapoptotic, prooxidative rac1 GTPase.

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“…Similar to other members of the receptor tyrosine kinase superfamily, the MET receptor contains three functionally distinct domains: a large ligand-binding domain derived from the extracellular ␣-subunit and the N-terminal portion of the ␤-subunit; a single hydrophobic transmembrane domain; and an intracellular tyrosine kinase domain (2,3). Activation of MET depends on receptor dimerization, which is induced by HGF stimulation.…”

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confidence: 99%

The SPRY Domain-containing SOCS Box Protein 1 (SSB-1) Interacts with MET and Enhances the Hepatocyte Growth Factor-induced Erk-Elk-1-Serum Response Element Pathway

Wang¹,

Li²,

Messing

et al. 2005

Journal of Biological Chemistry

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The suppressor of cytokine signaling (SOCS) protein family includes a SPRY (repeats in splA and RyR) domain-containing SOCS box protein (SSB) subfamily, which consists of four members, SSB-1, SSB-2, SSB-3, and SSB-4. These proteins contain a central SPRY domain and a C-terminal SOCS box. Although some of the SOCS protein subfamilies function as adaptors for a large family of ubiquitin-protein isopeptide ligases to regulate certain signaling pathways, the function of the SSB subfamily remains to be determined. In our previous studies, we have found that two SPRY domain-containing proteins, RanBP9 and RanBP10, interact with MET through the SPRY domain. In the present study, we explored the function of SSB proteins in the regulation of the hepatocyte growth factor (HGF)-MET signaling. Our results showed that all four SSB proteins also interacted with the MET. The MET interaction with SSB-1 was further investigated. We demonstrated that SSB-1 bound to MET tyrosine kinase domain through its SPRY domain. MET interacted with SSB-1 in both the absence and the presence of HGF, but HGF treatment resulted in the recruitment of more SSB-1 by MET. We showed that overexpression of SSB-1 but not other SSB proteins enhanced the HGF-induced serum response element (SRE)-luciferase activity. Overexpression of SSB-1 exhibited no effect on the basal level or epidermal growth factor-induced SRE-luciferase activity. SSB-1 also enhanced HGF-induced Erk phosphorylation. Suppression of SSB-1 by the RNA interference method down-regulated HGF-induced SRE-luciferase activity and decreased Elk-1 activation. These results suggest that SSB-1 may play an important role in enhancing the HGF-induced Erk-Elk-1-SRE pathway. Furthermore, we demonstrated that in response to HGF stimulation, the SSB-1 protein became phosphorylated at tyrosine residue 31. The phosphorylated SSB-1 protein bound to p120Ras-GTPase-activating protein (GAP) but did not promote the degradation of p120RasGAP, indicating that enhanced HGF-MET signaling by overexpression of SSB-1 was not dependent on p120RasGAP degradation.

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The hepatocyte growth factor/ met pathway in development, tumorigenesis, and B-cell differentiation

Cited by 98 publications

References 340 publications

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

The SPRY Domain-containing SOCS Box Protein 1 (SSB-1) Interacts with MET and Enhances the Hepatocyte Growth Factor-induced Erk-Elk-1-Serum Response Element Pathway

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