Abstract
Src family kinases (SFKs) are highly expressed and active in clinical glioblastoma multiforme (GBM) specimens. SFKs inhibitors have been demonstrated to inhibit proliferation and migration of glioma cells. However, the role of SFKs in glioma stem cells (GSCs), which are important for treatment resistance and recurrence, has not been reported. Here, we examined the expression pattern of individual members of SFKs and their functional role in CD133+ GSCs in comparison to primary glioma cells. We found that Fyn, c-Src and Yes were robustly expressed in GSCs while Lck was absent. Knockdown of c-Src, Yes or treatment with the SFK inhibitor dasatinib inhibited the migration of GSCs, but had no impact on their growth or self-renewal. These results suggest that SFKs represent an effective target for GSC migration but not for their growth.
Highlights
The Src family kinases (SFKs) are non-receptor tyrosine kinases that are membrane associated through a myristoylation site near their N-terminus
SFKs interact with multiple cell surface receptors including integrin, EGFR, PDGFR, VEGFR [2,3,7,8,9] and are activated rapidly upon receptor engagement resulting in the regulation of signaling events involving cell adhesion, migration, invasion, proliferation, apoptosis and angiogenesis [10,11]
SFKs are important kinases involved in glioma cell migration and invasion, and SFKs inhibitors have been in investigation for anti-glioma therapy
Summary
The Src family kinases (SFKs) are non-receptor tyrosine kinases that are membrane associated through a myristoylation site near their N-terminus. There are nine members in the family and five of which (Fyn, c-Src, Yes, Lyn and Lck) are expressed in human gliomas [1,2,3,4,5]. Each member of the SFKs contains a unique N-terminal sequence, followed by four SH (Src homology) domains, and a C-terminal negative regulatory sequence. Structural study of c-Src has revealed that intramolecular interactions occur between the phosphotyrosine 530 (pY530) in the C-terminus and the SH2 domain, and between the kinase domain and the SH3 domain, that cause the c-Src SFKs interact with multiple cell surface receptors including integrin, EGFR, PDGFR, VEGFR [2,3,7,8,9] and are activated rapidly upon receptor engagement resulting in the regulation of signaling events involving cell adhesion, migration, invasion, proliferation, apoptosis and angiogenesis [10,11]
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