Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells.
Bottom Line: NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling.Accordingly, both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib, a small molecule inhibitor of ABL1 which is widely used to prevent the proliferation of tumor cells that express BCR-ABL fusion proteins.The finding that NRP1 regulates angiogenesis in a VEGF- and VEGFR2-independent fashion via ABL1 suggests that ABL1 inhibition provides a novel opportunity for anti-angiogenic therapy to complement VEGF or VEGFR2 blockade in eye disease or solid tumor growth.
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: Because NRP1 lacks catalytic activity, it requires a partner kinase to promote FN-induced PXN phosphorylation, but this kinase is not VEGFR2 (Fig. 1) or FAK (Fig. 2, B and C). A good candidate is the cell adhesion–associated kinase ABL1, which interacts with PXN in FN-stimulated fibroblasts (Lewis and Schwartz, 1998) as well as integrins β1 and β2 (Cui et al., 2009; Baruzzi et al., 2010). Furthermore, the Y118 residue that is phosphorylated in an NRP1-dependent fashion resides in an ABL1 phosphorylation consensus site (Cujec et al., 2002), and ABL1 is an effector of NRP1 and integrins in tumor matrix remodeling (Yaqoob et al., 2012). To investigate ABL1 function in FN-stimulated ECs, we used two independent but complementary methods: siRNA-mediated knockdown of ABL1 (Fig. 4) and pharmacological inhibition of ABL1 kinase activity (Fig. 5).
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.