Emaduddin M, Bicknell DC, Bodmer WF, Feller SM.. Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells. Proc Natl Acad Sci USA 105: 2358-2362

Cell Signalling Group and Cancer and Immunogenetics Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2008; 105(7):2358-62. DOI: 10.1073/pnas.0712176105
Source: PubMed


The heterogeneity of cancer cell signaling is a significant obstacle for the effective development and clinical use of molecularly targeted therapies. As a contribution to a better understanding of the diversity of signaling activities in colorectal cancers (CRCs), we have analyzed the activity of Src family kinases (SFKs), which are implicated in human cancer development, in 64 CRC cell lines. A striking diversity of SFK activity was observed within this panel. Importantly, all CRC lines tested depend on SFK activity for their growth. In addition, SFK activity levels strongly correlated with global levels of tyrosine-phosphorylated (pTyr) proteins in CRC lines. SFK inhibition substantially reduced these pTyr levels, suggesting that SFKs may function as signal integration points and master controllers for the pTyr protein status in CRC lines. The majority of analyzed CRC lines with high-SFK activity express activated c-Met (pYpY1234/1235), a receptor tyrosine kinase contributing to the regulation of cell proliferation, migration, and invasion. Inhibition of SFKs reduced c-Met phosphorylation in most cases, indicating a reversed signal flow from SFK to c-Met. We conclude that SFK activity is important for the growth of CRC lines, although only low activity levels are required. If this also is true for CRC patients, tumors with low-SFK activity may be particularly sensitive to SFK inhibitors, and such patients should be targeted in clinical trials testing SFK inhibitors.

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    • "tor could oligomerize with MET . This was ruled out by lack of receptor co - precipitation , and by lack of receptor co - localization after fluorescent immunostaining and confocal microscopy . We can also hypothesize that MET phosphorylation is mediated by an intracellular kinase . A likely candidate is SRC , which is known to phosphorylate MET ( Emaduddin et al . , 2008 ) , and can be activated by the TNF Receptor ( Pincheira et al . , 2008 ) . Indeed , in A549 cells , TNF - a activated SRC , and invasion promoted by TNF - a was prevented by the specific SRC inhibitor Saracatinib ( Bertotti et al . , 2010 ) , but modulation of MET phosphorylation was barely detectable . These findings suggest that SRC "
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    Molecular Oncology 09/2014; DOI:10.1016/j.molonc.2014.09.002 · 5.33 Impact Factor
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    • "In addition, the cross-talk between c-Met and other signaling molecules post-transcriptionally could be a possibility given that c-Met is able to be transactivated by several other transmembrane proteins [35]. In the PC-3 cell line, basal c-Met phosphorylation remained unaffected by exposure to either gefitinib or dasatinib (data not shown), suggesting that c-Met is not activated by epidermal growth factor receptor (EGFR) or c-Src, two kinases shown to be involved in c-Met transactivation in some studies [36,37]. However other signaling molecules such as Ron, another Met receptor family member which is also overexpressed in PC-3 cells [38], might transactivate c-Met. "
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    • "Recent studies looking at 64 individual CRC cell lines found a striking diversity of SFK activity. The authors reported that all lines tested depended on SFK activity for growth and concluded from this work SFK activity is important for the growth of CRC lines (Emaduddin et al., 2008). In addition to SFK activity and CRC progression, SFK activity has been reported as a marker of poor clinical prognosis (Aligayer et al., 2002). "
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