Targeting Lyn tyrosine kinase through protein fusions encompassing motifs of Cbp (Csk-binding protein) and the SOCS box of SOCS1

The Biochemical Journal
Rhiannon J WhitingEvan Ingley

Abstract

The tyrosine kinase Lyn is involved in oncogenic signalling in several leukaemias and solid tumours, and we have previously identified a pathway centred on Cbp [Csk (C-terminal Src kinase)-binding protein] that mediates both enzymatic inactivation, as well as proteasomal degradation of Lyn via phosphorylation-dependent recruitment of Csk (responsible for phosphorylating the inhibitory C-terminal tyrosine of Lyn) and SOCS1 (suppressor of cytokine signalling 1; an E3 ubiquitin ligase). In the present study we show that fusing specific functional motifs of Cbp and domains of SOCS1 together generates a novel molecule capable of directing the proteasomal degradation of Lyn. We have characterized the binding of pY (phospho-tyrosine) motifs of Cbp to SFK (Src-family kinase) SH2 (Src homology 2) domains, identifying those with high affinity and specificity for the SH2 domain of Lyn and that are preferred substrates of active Lyn. We then fused them to the SB (SOCS box) of SOCS1 to facilitate interaction with the ubiquitination-promoting elongin B/C complex. As an eGFP (enhanced green fluorescent protein) fusion, these proteins can direct the polyubiquitination and proteasomal degradation of active Lyn. Expressing this fusion protein in...Continue Reading

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Citations

Nov 12, 2013·Oncogene·M Hrdinka, V Horejsi
Jun 26, 2014·Gene Expression Patterns : GEP·Vanesa Zazueta-Novoa, Gary M Wessel
Oct 19, 2016·Experimental Hematology·Janice H C Plani-LamEvan Ingley
Jan 15, 2015·Molecular & Cellular Proteomics : MCP·Lily L JinMichael F Moran
Mar 20, 2016·Oncotarget·Saurabh AgarwalJason M Shohet

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