Activating SRC mutation in a subset of advanced human colon cancers

Irby, Rosalyn; Mao, Weiguang; Coppola, Domenico; Kang, Jimmy J H; Loubeau, Jean Marc; Trudeau, Walter L.; Karl, Richard C.; Fujita, Daishi; Jove, Richard; Yeatman, Timothy J.

doi:10.1038/5971

Cited by 437 publications

(337 citation statements)

References 26 publications

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“…In normal cells, the kinase activity of c-Src is rigorously controlled by the negative regulator, C-terminal Src kinase (Csk) (Okada et al, 1991); thus, even when c-Src is abundantly expressed, its oncogenic potential is suppressed. The c-src gene is rarely mutated, but c-Src function is nonetheless upregulated in some cancer cells (Irby et al, 1999;Irby and Yeatman, 2000). Therefore, it has been hypothesized that disruption of the strict regulation of c-Src signaling triggers cancer progression, although the underlying mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

et al. 2011

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The tyrosine kinase c-Src is upregulated in various human cancers; however, the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. Here we show that downregulation of microRNA (miR)-542-3p is tightly associated with tumor progression via c-Src-related oncogenic pathways. In c-Src-transformed fibroblasts and human cancer cells that overexpress c-Src, miR-542-3p is substantially downregulated, and the ectopic expression of miR-542-3p suppresses tumor growth. We identified the integrin-linked kinase (ILK) as a conserved target of miR-542-3p. ILK upregulation promotes cell adhesion and invasion by activating the integrin-focal adhesion kinase (FAK)/c-Src pathway, and can also contribute to tumor growth via the AKT and glycogen synthase kinase 3b pathways. MiR-542-3p expression is downregulated by the activation of c-Src-related signaling molecules, including epidermal growth factor receptor, K-Ras and Ras/ Raf/mitogen-activated protein kinase/extracellular signalregulated kinase. In human colon cancer tissues, downregulation of miR-542-3p is significantly correlated with the upregulation of c-Src and ILK. Our results suggest that the novel c-Src-miR-542-3p-ILK-FAK circuit plays a crucial role in controlling tumor progression.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

et al. 2011

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“…In contrast to Ras, Src activation by mutation is a rare event, suggesting the existence of alternative mechanisms for oncogenesis (Irby et al, 1999). Kinase activation often correlates with protein overexpression (Yeatman, 2004), but overexpression alone in a normal cellular context is not sufficient to induce cell transformation, as SFK are subjected to strict regulation that maintain the enzymes in an inactive form.…”

Section: Introductionmentioning

confidence: 99%

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

et al. 2009

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The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/ phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Cskdependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.

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“…The tetramer : dimer ratio of M2-PK is under the control of several oncoproteins, such as pp60 vÀsrc kinase, HPV-16 E7 and A-Raf ( Figure 1B) (Eigenbrodt et al, 1998b;Zwerschke et al, 1999;Le Mellay et al, 2002). Interestingly, pp60 cÀsrc kinase and A-Raf are consistently altered in gastrointestinal tumours (Bolen et al, 1987;Iravani et al, 1998;Irby et al, 1999;Luckett et al, 2000;Dehm et al, 2001;Dhillon et al, 2003).…”

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confidence: 96%

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer

et al. 2004

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Proliferating cells, especially tumour cells, express a special isoenzyme of pyruvate kinase, termed M2-PK, which can occur in a tetrameric form with a high affinity to its substrate, phosphoenolpyruvate (PEP), and in a dimeric form with a low PEP affinity. In tumour cells, the dimeric form is usually predominant and is therefore termed Tumour M2-PK. The levels of Tumour M2-PK within tumours and in EDTA-plasma correlate with staging and the ability of the tumour cells to metastasise. Since most colorectal tumours grow intraluminally, it appeared interesting to determine whether Tumour M2-PK is detectable in the faeces of tumour patients. Stool samples were tested by ELISA from controls without colorectal cancer and colorectal cancer patients. Whereas Tumour M2-PK levels were low in the control group (mean value7s.e.m.: 3.370.4, n ¼ 144), they were high in the case of colorectal cancer (56.1715.3, n ¼ 60). At a cutoff value of 4 U ml À1 , the sensitivity was 73%. TNM and Dukes' classification of the tumours revealed a strong correlation between faecal Tumour M2-PK levels and staging. The determination of Tumour M2-PK in faeces provides a new promising screening tool for colorectal tumours.

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Activating SRC mutation in a subset of advanced human colon cancers

Cited by 437 publications

References 26 publications

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer

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