Nuclear localization of active HGF receptor Met in aggressive MDA-MB231 breast carcinoma cells
Authors: Maria Alfonsina Desiderio
Emanuela Matteucci
Paola Bendinelli
Journal: Carcinogenesis (2009)
Discipline: CLINICAL MEDICINE
Keywords: Hepatocyte growth factor; Met system; breast carcinoma cells; Met cytosolic fragments; Wwox tumor suppressor
Affiliations: Dipartimento di Morfologia Umana e Scienze Biomediche 'Città Studi', University of Milan, Italy.

Abstract:  Hepatocyte growth factor (HGF)/Met system is deregulated in tumors and is implicated in different aspects of invasive growth. Here, we report that in the highly aggressive MDA-MB231 breast carcinoma cells, Met cytosolic fragments [C-terminal fragment (CTF)] were present in the nuclei. They were constitutively active because tyrosine phosphorylated at regulatory and catalytic domains and endowed with transactivating activity independently of HGF exposure. In fact, various constructs containing juxtamembrane (Jxtm) Met fragments, fused with Gal4 DNA-binding domain, transactivated Gal4Luc activity. MDA-MB231 cells were devoid of WW domain-containing oxidoreductase (Wwox) tumor suppressor. Exogenous Wwox protein expression negatively regulated Jxtm3-transactivating activity and decreased spontaneous migration of MDA-MB231 cells. Also, we demonstrate that the lack of endogenous Wwox in MDA-MB231 cells represented a molecular mechanism for intranuclear Met-CTF accumulation and for the decrease of full-length Met stability. Yes-associated proteins maintained constitutively activated nuclear Met fragments that played a role as transcription factors regulating genes probably including those for motile phenotype. The difference with low invasive MCF-7 cells was evident because the latter did not show intranuclear Met and the transfected constructs-containing Jxtm fragments were inactive also in the presence of HGF. The constitutive activation of nuclear Met-signaling pathway in MDA-MB231 cells, possibly determined at genetic or epigenetic levels of WWOX gene, might participate in breast carcinoma progression influencing invasive/metastatic phenotype. Wwox/Met system can be suggested as a potential target to impair breast carcinoma progression. 

Retracted: No

PubPeer comments:
 #2 HDAC1, Figure 5 Mol Cancer Res: when you compare the original pictures in the two articles, it is possible to appreciate that the 3 evidenced (yellow) bands are not the same of those in Figure 5 Carcinogenesis. In fact, in the original pictures they show different thickness. HDAC3, Figure 5 Mol Cancer Res: the vinculin shows some differences from that of MDA-MB231 cells in Figure 5 Carcinogenesis. In the latter Figure, the two bands indicated (red) are not stretched in respect to those of Mol Cancer Res; in any case the two vinculin (green square) show differences in the lateral band on the right, and so they cannot be the same. , 
 ![file] , 
 Figure 2A continued. ![file] , 
 There are additional unusual features to see in Fig 2A (contrast enhanced): ![file] , 
null, 
null, 
 ![file] , 
 More from the Department of Unexpected Similarities. At right: (part of) Fig 5A. At left: Fig 1B from [Maroni et al (2015)] . ![file] , 
 Figure 4A: At right I have flipped the vinculin band horizontally for comparison with the loading controls from two panels of Fig 8(d) of [Maroni et al (2014)] . ![file] ,