Overexpression of the Hepatocyte Growth Factor (HGF) Receptor (Met) and Presence of a Truncated and Activated Intracellular HGF Receptor Fragment in Locally Aggressive/Malignant Human Musculoskeletal Tumors

Wallenius, Ville; Hisaoka, Masanori; Helou, Khalil; Levan, Göran; Mandahl, Nils; Meis‐Kindblom, Jeanne M.; Kindblom, Lars Gunnar; Jansson, John Olov

doi:10.1016/s0002-9440(10)64950-4

Cited by 73 publications

(69 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, it could even be used for studies of ErbB2 cleavage in transgene animals. Cleavage is also an important regulator of other proteins, e.g., ErbB4, Met, Notch, CD44, p75/NTR, and APP (Selkoe et al, 1996;Haass and De, 1999;Wallenius et al, 2000;Ni et al, 2001;Zampieri et al, 2005;Petrelli et al, 2006;Sugahara et al, 2006), and tandem fusion proteins made from these proteins similarly to YEC could be highly useful. An important advantage of such constructs is that one avoids the problems inherent to ratiometric studies based on immunofluorescence, namely availability of protein epitopes and steric hindrance.…”

Section: Discussionmentioning

confidence: 99%

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Lerdrup

Bruun

Grandal

et al. 2007

MBoC

View full text Add to dashboard Cite

High ErbB2 levels are associated with cancer, and impaired endocytosis of ErbB2 could contribute to its overexpression. Therefore, knowledge about the mechanisms underlying endocytic down-regulation of ErbB2 is warranted. The Cterminus of ErbB2 can be cleaved after various stimuli, and after inhibition of HSP90 with geldanamycin this cleavage is accompanied by proteasome-dependent endocytosis of ErbB2. However, it is unknown whether C-terminal cleavage is linked to endocytosis. To study ErbB2 cleavage and endocytic trafficking, we fused yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) to the N-and C-terminus of ErbB2, respectively (YFP-ErbB2-CFP). After geldanamycin stimulation YFP-ErbB2-CFP became cleaved in nonapoptotic cells in a proteasome-dependent manner, and a markedly larger relative amount of cleaved YFP-ErbB2-CFP was observed in early endosomes than in the plasma membrane. Furthermore, cleavage took place at the plasma membrane, and cleaved ErbB2 was internalized and degraded far more efficiently than full-length ErbB2. Concordantly, a C-terminally truncated ErbB2 was also readily endocytosed and degraded in lysosomes compared with full-length ErbB2. Altogether, we suggest that geldanamycin leads to C-terminal cleavage of ErbB2, which releases the receptor from a retention mechanism and causes endocytosis and lysosomal degradation of ErbB2. INTRODUCTIONThe receptor tyrosine kinase ErbB2 is a potent oncoprotein, and a high ErbB2 level can by itself activate ErbB receptors (Worthylake et al., 1999). Concordantly, increased ErbB2 levels can be found in several cancers (Klapper et al., 2000;Yarden, 2001), and high ErbB2 levels are correlated to a worse prognosis for breast cancer patients (Slamon et al., 1987;Hynes and Stern, 1994;De Placido et al., 1998;Pegram et al., 1998). Gene amplification is the most studied mechanisms causing high ErbB2 levels, but also posttranscriptional regulation of ErbB2 plays a role in cancers (Vernimmen et al., 2003;Magnifico et al., 2007). Little attention has been paid to the role of ErbB2 degradation in cancers, although when compromised it also would lead to increased ErbB2 levels and activity. Several studies have shown that endocytic downregulation of ErbB2 is impaired in cancer cells (Sorkin et al., 1993; Baulida et al., 1996;Wang et al., 1999;Hommelgaard et al., 2004;Austin et al., 2004;Longva et al., 2005), and ErbB2 can even transmit this property to the related epidermal growth factor receptor (EGFR; Muthuswamy et al., 1999;Wang et al., 1999;Worthylake et al., 1999;Haslekas et al., 2005). Inhibition of HSP90 (e.g., with geldanamycin [GA]) leads to increased internalization and lysosomal degradation of ErbB2 in a manner depending on proteasomal activity (Tikhomirov and Carpenter, 2000;Austin et al., 2004;Lerdrup et al., 2006). HSP90 inhibition also induces cleavage of the cytoplasmic part of ErbB2, resulting in a transmembrane 135-kDa ErbB2 and short-lived cytoplasmic fragments (Tikhomirov and Carpenter, 2000;Lerdrup et al., 2006). The cleavage oc...

show abstract

Section: Discussionmentioning

confidence: 99%

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Lerdrup

Bruun

Grandal

et al. 2007

MBoC

View full text Add to dashboard Cite

show abstract

“…Other receptor tyrosine kinases are expressed as truncated forms in malignant cells, but usually these aberrant proteins are constitutively active kinases in which the catalytic domain is freed by negative constraints present in the full-length receptor. [7][8][9] By contrast, the truncated c-Kit protein does not contain an ATP binding site and should be catalytically inactive. 5 Our laboratory has previously described that a mouse homologue of the truncated human c-Kit is physiologically expressed only in the postmeiotic haploid cells of the testis; 10 more recently we have detected human tr-Kit also in human mature spermatozoa, indicating a conserved role of this protein in gamete function (Paronetto MP, Geremia R, Rossi P, and Sette C, manuscript in preparation).…”

mentioning

confidence: 99%

Expression of a Truncated Form of the c-Kit Tyrosine Kinase Receptor and Activation of Src Kinase in Human Prostatic Cancer

Paronetto

Farini

Sammarco

et al. 2004

The American Journal of Pathology

View full text Add to dashboard Cite

The c-Kit receptor belongs to type III tyrosine kinase receptor, which consists of an extracellular ligand binding domain and an intracellular kinase domain. In the kinase domain, the ATP binding site is separated from the phosphotransferase site by an interkinase sequence required for interaction with signal transduction proteins involved in the c-Kit pathway. 1 The c-Kit receptor is expressed in a wide variety of normal and neoplastic tissues. A positive correlation between misregulation of the c-kit gene and malignant transformation of cells has been reported. 2,3 For instance, substitution mutations in exon 11 of the gene, changing amino acids of the juxtamembrane region of the receptor, are associated with gastrointestinal stromal tumors, whereas mutations in exon 17 that substitute Asp816, just downstream of the tyrosine kinase signature, are associated with myeloid leukemias and testicular seminomas. 2,3 These mutations induce ligand-independent dimerization or autophosphorylation of the receptor and they cause constitutive activation of downstream signaling pathways. Moreover, overexpression of c-Kit and its ligand SCF occurs in several tumors and they probably stimulate proliferation in an autocrine or paracrine manner. 2 Recently, c-kit expression in various tumors has been revisited because this receptor is a target of the anti-cancer activity of a well described tyrosine kinase inhibitor: imatinib (STI1571). 2,4 Beside mutations affecting the activity of the full-length c-Kit, expression of an alternative transcript of human c-kit has been described in several transformed cell lines. The

show abstract

“…We and other have shown that the MET oncogene is aberrantly overexpressed in approximately 80% of all subtypes of human osteosarcomas, (3)(4)(5)(6)(7)31) although it is almost not detectable in other mesenchyme-derived tumors, such as fibrosarcoma and chondrosarcoma, as well as in adult tissues of mesenchymal origin. (3)(4)(5)(6)(7) To study MET-induced transformation of cells derived from mesenchymal lineages, we overexpressed the MET oncogene in primary cultures of human bone-derived cells and obtained MET overexpressing osteosarcoma (MET-OS) clones.…”

Section: Resultsmentioning

confidence: 99%

“…(3)(4)(5)(6)(7) To study MET-induced transformation of cells derived from mesenchymal lineages, we overexpressed the MET oncogene in primary cultures of human bone-derived cells and obtained MET overexpressing osteosarcoma (MET-OS) clones. (26) As previously reported, the MET-OS clones originated from independent and multiple events of MET transgene integration into cultured cells.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, we and others have shown that the MET oncogene is aberrantly overexpressed in a high percentage of human osteosarcomas, whereas it is almost not detectable in other mesenchyme-derived tumors, as well as in adult tissues of mesenchymal origin. (3)(4)(5)(6)(7) Osteosarcomas are rare primary bone tumors, which occur primarily in children and adolescents (for review, see (8) ). Classically, they are defined by the production of an abnormal osteoid matrix, although most osteosarcomas are histopathologically graded as poorly differentiated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors

Dani

Olivero

Mareschi

et al. 2012

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The MET oncogene is aberrantly overexpressed in human osteosarcomas. We have previously converted primary cultures of human bone-derived cells into osteosarcoma cells by overexpressing MET. To determine whether MET transforms mesenchymal stem cells or committed progenitor cells, here we characterize distinct MET overexpressing osteosarcoma (MET-OS) clones using genome-wide expression profiling, cytometric analysis, and functional assays. All the MET-OS clones consistently display mesenchymal and stemness markers, but not most of the mesenchymal-stem cell-specific markers. Conversely, the MET-OS clones express genes characteristic of early osteoblastic differentiation phases, but not those of late phases. Profiling of mesenchymal stem cells induced to differentiate along osteoblast, adipocyte, and chondrocyte lineages confirms that MET-OS cells are similar to cells at an initial phase of osteoblastic differentiation. Accordingly, MET-OS cells cannot differentiate into adipocytes or chondrocytes, but can partially differentiate into osteogenic-matrix-producing cells. Moreover, in vitro MET-OS cells form self-renewing spheres enriched in cells that can initiate tumors in vivo. MET kinase inhibition abrogates the self-renewal capacity of MET-OS cells and allows them to progress toward osteoblastic differentiation. These data show that MET initiates the transformation of a cell population that has features of osteo-progenitors and suggest that MET regulates self-renewal and lineage differentiation of osteosarcoma cells. ß

show abstract

Overexpression of the Hepatocyte Growth Factor (HGF) Receptor (Met) and Presence of a Truncated and Activated Intracellular HGF Receptor Fragment in Locally Aggressive/Malignant Human Musculoskeletal Tumors

Cited by 73 publications

References 29 publications

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Expression of a Truncated Form of the c-Kit Tyrosine Kinase Receptor and Activation of Src Kinase in Human Prostatic Cancer

The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors

Contact Info

Product

Resources

About