The interplay between Src family kinases and receptor tyrosine kinases

Bromann, Paul Andrew; Korkaya, Hasan; Courtneidge, Sara A.

doi:10.1038/sj.onc.1208079

Cited by 413 publications

(402 citation statements)

References 155 publications

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“…We describe here that activation of c-Src might be mediated by activation of the EGFR (Figures 5 and 6), Src activation being required for full Akt activation and survival ( Figure 6). Src family tyrosine kinases are activated by tyrosine kinase receptors and, in turn, can promote signalling from growth factor receptors in a number of ways including DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangements, motility and survival (Bromann et al, 2004). There are many reports indicating that c-Src protein expression and/or activity is elevated in epithelial cancers (Biscardi et al, 1999) and activation of c-Src in hepatocellular carcinoma cells is highly correlated with the indices of early-stage phenotype (Ito et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes

et al. 2005

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Transforming growth factor beta1 (TGF-b1) belongs to a family of polypeptide factors, whose cytostatic and apoptotic functions help restrain the growth of mammalian cells. Although solid data established the role of TGF-b's as suppressor factors in tumorigenic processes, in the context of an advanced stage of disease, TGF-b's could also play a pro-oncogenic role. We have previously shown that TGF-b1 induces both pro-and antiapoptotic signals in foetal rat hepatocytes. In this work, we have focused on its antiapoptotic mechanism. We show that TGF-b1 activates the epidermal growth factor receptor (EGFR) and phosphorylates c-Src. EGFR is required for Akt activation. Blocking EGFR signalling amplifies the apoptotic response to TGF-b1. TGF-b1 induced a rapid activation of the tumour necrosis factor-a-converting enzyme (TACE/ADAM (a disintegrin and metalloprotease) 17). Inhibitors of TACE considerably attenuated Akt activation, which suggests that TGF-b1 activates EGF signalling in hepatocytes by promoting shedding of EGF-like ligands. The activation of c-Src by TGF-b1 is EGFR dependent and is required for full Akt phosphorylation and cell survival. Inhibition of EGFR does not block the epithelial-mesenchymal transition (EMT) induced by TGF-b1 in hepatocytes, which indicates that activation of EGFR plays an essential role in impairing apoptosis, but it is dispensable for the EMT process.

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Section: Discussionmentioning

confidence: 99%

Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes

et al. 2005

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“…Aberrant expression and activation of src-family kinases have been implicated in a number of human malignancies but thus far they have not proven to be effective clinical targets [12][13]. Despite this, molecular studies continue to show src to play a potential role in clinically important pathways in breast cancer including the steroid and peptide hormone signaling pathways [14][15].…”

Section: Introductionmentioning

confidence: 99%

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

Finn

Dering

Ginther

et al. 2007

Breast Cancer Res Treat

367

284

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Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-tomesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 lM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40-59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (v 2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with ''triplenegative'' breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

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“…17 SFK are thought to interact with a cell surface receptor and participate in initial signal transduction via this receptor. 18 It is reported that several RTK, including c-Fms, PDGF receptor b, c-Kit, and epidermal growth factor receptor (EGFR), activate SFK. 18,19 Also, SFK have been reported to activate STAT pathways and play a role in cytokine-induced cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…18 It is reported that several RTK, including c-Fms, PDGF receptor b, c-Kit, and epidermal growth factor receptor (EGFR), activate SFK. 18,19 Also, SFK have been reported to activate STAT pathways and play a role in cytokine-induced cell proliferation. 20 Originally Lyn was cloned as a signal component of B-cell antigen receptor, but recent studies revealed that Lyn also acted as a signal component of cytokine receptors such as erythropoietin receptor, CSF-1 receptor, and c-Kit, and promoted mitogenic signaling from them.…”

Section: Introductionmentioning

confidence: 99%

Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD

et al. 2007

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Fms-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells. An internal tandem duplication (ITD) of FLT3 (FLT3/ITD) is the most frequent mutation in human adult acute myeloid leukemia (AML). FLT3/ITD contributes to the constitutive activation of FLT3 itself and its downstream signal components, mitogen-activated protein kinase and signal transducers and activators of transcription 5 (STAT5), and enables interleukin (IL)-3-dependent cell lines to grow autonomously. In the present study, we showed the specific association of FLT3/ITD with Lyn, which led to the phosphorylation of Lyn in vivo. We also demonstrated that FLT3/ITD receptors displayed a higher affinity to bind to Lyn than wild-type FLT3 receptors in vitro and that this affinity was relative to the intensity of tyrosil phosphorylation of the receptor. Both treatment with small interfering RNA (siRNA) targeting Lyn and the Src family kinase inhibitor PP2 suppressed the IL-3-independent growth of FLT3/ITD-expressing 32D cells (FLT3/ ITD-32D), reducing the constitutive phosphorylation of Lyn and STAT5. PP2 treatment of mice transplanted with FLT3/ITD-32D cells blocked the onset of tumors and decreased the size of established tumors. These results demonstrate that Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.

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The interplay between Src family kinases and receptor tyrosine kinases

Cited by 413 publications

References 155 publications

Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes

Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD

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