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American Journal of Cancer Research (1)
The Journal of Cell Biology (1)
Benistant, Christine (2)
Roche, Serge (2)
Horejsi, Vaclav (1)
Richard, Véronique (1)
Schraven, Burkhart (1)
Simon, Valérie (1)
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Veracini, Laurence (1)
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Oncogenic signaling by tyrosine kinases of the SRC family in advanced colorectal cancer
American Journal of Cancer Research
The non-receptor tyrosine kinases of the SRC family (SFK) play important roles in signal transduction induced by a large variety of extracellular stimuli, including growth factors and Integrins. When deregulated, SFKs show oncogenic activity, as originally reported for v-Src, the transforming product of the avian retrovirus RSV, and then, in many human cancers, particularly colorectal cancer (CRC). In CRC, SFK deregulation largely occurs in the absence of mutations of the corresponding genes, but the underlying molecular mechanisms involved are still unclear. In addition to a role in early tumor progression, SFK deregulation may also be important in advanced CRC, as suggested by the association between increased SFK activity and poor clinical outcome. However, SFK contribution to CRC metastasis formation is still poorly documented. Here, we will review recent findings that broaden our understanding of the mechanisms underlying SFK deregulation and signaling in advanced CRC. We will also discuss the implication of these observations for SFK-based therapy in metastatic CRC.
Non-receptor tyrosine kinases; signal transduction; colorectal cancer (CRC); early tumor progression; advanced CRC
The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1
The Journal of Cell Biology
Spatial regulation is an important feature of signal specificity elicited by cytoplasmic tyrosine kinases of the Src family (SRC family protein tyrosine kinases [SFK]). Cholesterol-enriched membrane domains, such as caveolae, regulate association of SFK with the platelet-derived growth factor receptor (PDGFR), which is needed for kinase activation and mitogenic signaling. PAG, a ubiquitously expressed member of the transmembrane adaptor protein family, is known to negatively regulate SFK signaling though binding to Csk. We report that PAG modulates PDGFR levels in caveolae and SFK mitogenic signaling through a Csk-independent mechanism. Regulation of SFK mitogenic activity by PAG requires the first N-terminal 97 aa (PAG-N), which include the extracellular and transmembrane domains, palmitoylation sites, and a short cytoplasmic sequence. We also show that PAG-N increases ganglioside GM1 levels at the cell surface and, thus, displaces PDGFR from caveolae, a process that requires the ganglioside-specific sialidase Neu-3. In conclusion, PAG regulates PDGFR membrane partitioning and SFK mitogenic signaling by modulating GM1 levels within caveolae independently from Csk.
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