Non-cytotoxic, potent and specific UNC119-cargo interation blocker that inhibits Lck localization at T-cell immune synpase and Src activation.
Squarunkin A is a non-cytotoxic, potent and specific UNC119-cargo interation blocker (IC50 = 10 nM against 800 nM myristoylated Src N-terminal peptide for GST-UNC119A) that targets UNC119A/B myristoyl-binding pocket without affecting the interaction of geranylgeranylated Rab1 to RhoGDI22, or farnesylated Rheb to PDE6d, AIPL1, and calmodulin. Squarunkin A blocks Lck localization at staphylococcal E enterotoxin-induced Jurkat T-cell synpase (2 μM) and prevents MDA-MB-231 cellular Src activation (37/62% reduced Src pY416 post 24 hr 78/625 nM Squarunkin A incubation) without growth inhibition or apoptosis induction (10 μM for >35 hrs).
Angewandte Chemie (International ed. in English), 56(22), 6181-6186 (2017-05-05)
N-Terminal myristoylation facilitates membrane binding and activity of proteins, in particular of Src family kinases, but the underlying mechanisms are only beginning to be understood. The chaperones UNC119A/B regulate the cellular distribution and signaling of N-myristoylated proteins. Selective small-molecule modulators
Chembiochem : a European journal of chemical biology, 19(14), 1482-1487 (2018-04-28)
Plasma membrane localization of myristoylated c-Src, a proto-oncogene protein-tyrosine kinase, is required for its signaling activity. Recent studies proposed that UNC119 protein functions as a solubilizing factor for myristoylated proteins, thereby regulating their subcellular distribution and signaling. The underlying molecular
Upon engagement of the T cell receptor with an antigen-presenting cell, LCK initiates TCR signaling by phosphorylating its activation motifs. However, the mechanism of LCK activation specifically at the immune synapse is a major question. We show that phosphorylation of the
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