Src signaling in cancer invasion

Abstract

Src is a non-receptor cytoplasmic tyrosine kinase which becomes activated following the stimulation of plasma membrane receptors including receptor tyrosine kinases and integrins, and is an indispensable player of multiple physiological homeostatic pathways. Once activated, Src is the starting point for several biochemical cascades that thereby propagate signals generated extracellularly along intracellular interconnected transduction pathways. Src transmits signals promoting cell survival and mitogenesis and, in addition, exerts a profound effect on the reorganization of the cytoskeleton and the adhesion systems that underpin cell migration and invasion. Because increased activity of Src is a frequent occurrence in many types of human cancer, and because there is evidence of a prominent role of Src in invasion and in other tumor progression-related events such as epithelial-mesenchymal transition (EMT) and development of metastasis, inhibitors targeting Src are being viewed as promising drugs for cancer therapy.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…The activated kinase c-Src, a well characterised EMT inducer [72] and its downstream targets, such as fibronectin, p-Fak and p-Stat3 were not expressed in small intramucosal foci of SRCCs, while the immunoreactivity was observed in dedifferentiated neoplastic cells in larger intramucosal lesions, and in advanced HDGCs with increased depth of invasion. These findings, however, could not be confirmed by Barber et al [68].…”

Apoptosis-associated tyrosine kinase 1 inhibits growth and migration and promotes apoptosis in melanoma

“…When Y530 is dephosphorylated, the SH2 and SH3 domains are released from the intramolecular interactions and the open conformation allows the phosphorylation of Y419 in the activation loop to enhance the catalytic activity. 24 Activation of Src correlates with Y419 levels. Our results revealed an inverse correlation between the activation of SRC and expression of AATK in COLO829 and MeWo cells, which implicates SRC in AATK function in melanoma cells.…”

Src Points the Way to Biomarkers and Chemotherapeutic Targets

“…Furthermore, Src leads to the disruption of the actin cytoskeleton as well as cell-cell and cell-matrix adhesions. 20,21 This disruption of the microenvironment and intercellular communication may lead to loss of contact growth inhibition that is also exhibited by many transformed cells.…”

“…Src is composed of several functional domains 21,25 that are illustrated in Figure 1. The N-terminal region of Src contains an SH4 (Src homology 4) domain and is myristoylated, which is required for association with the inner side of the cell membrane.…”

“…However, the kinase activity and transforming ability of c-Src is negatively regulated by phosphorylation at Tyr527 (Tyr530 in humans), which is absent in v-Src. 21,29,30 Src is clinically relevant as it plays an important role in oncogenesis. Although Src expression and its specific activity are frequently elevated in a number of human cancers, it is rarely mutated.…”