Odin (ANKS1A) is a Src family kinase target in colorectal cancer cells

Abstract

BackgroundSrc family kinases (SFK) are implicated in the development of some colorectal cancers (CRC). One SFK member, Lck, is not detectable in normal colonic epithelium, but becomes aberrantly expressed in a subset of CRCs. Although SFK have been extensively studied in fibroblasts and different types of immune cells, their physical and functional targets in many epithelial cancers remain poorly characterised.Results64 CRC cell lines were tested for expression of Lck. SW620 CRC cells, which express high levels of Lck and also contain high basal levels of tyrosine phosphorylated (pY) proteins, were then analysed to identify novel SFK targets. Since SH2 domains of SFK are known to often bind substrates after phosphorylation by the kinase domain, the LckSH2 was compared with 14 other SH2s for suitability as affinity chromatography reagent. Mass spectrometric analyses of LckSH2-purified pY proteins subsequently identified several proteins readily known as SFK kinase substrates, including cortactin, Tom1L1 (SRCASM), GIT1, vimentin and AFAP1L2 (XB130). Additional proteins previously reported as substrates of other tyrosine kinase were also detected, including the EGF and PDGF receptor target Odin. Odin was further analysed and found to contain substantially less pY upon inhibition of SFK activity in SW620 cells, indicating that it is a formerly unknown SFK target in CRC cells.ConclusionRapid identification of known and novel SFK targets in CRC cells is feasible with SH2 domain affinity chromatography. The elucidation of new SFK targets like Odin in epithelial cancer cells is expected to lead to novel insight into cancer cell signalling mechanisms and may also serve to indicate new biomarkers for monitoring tumor cell responses to drug treatments.

XB130, a Novel Adaptor Protein, Promotes Thyroid Tumor Growth

“…In addition to TPC-1 and WRO thyroid cancer cells, we observed similar effects of XB130 down-regulation on the proliferation and survival of A549 cells, a human lung carcinoma cell line (data not shown). It is interesting that a study by Emaduddin and colleagues 32 investigating the implications of Src tyrosine kinases in certain colorectal cancers distinguished XB130 from SW629 colorectal cancer cells as being one of the tyrosine phosphorylated proteins binding to the Lck-SH2 domain. Lck is an Src family member that is not detectable in normal colonic epithelium but becomes aberrantly expressed in a subset of colorectal carcinomas.…”

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

“…Our fifth candidate locus is lung cancer risk gene (18) ANKS1A, also known as ODIN, a Src kinase that negatively regulates growth factor signaling (19). ANKS1A interacts with and is phosphorylated by Lck (lymphocyte-specific protein tyrosine kinase) (20), a critical component of T-cell activation. rs2820223 of ANKS1A was associated (P ¼ 3.5Â10…”

Adaptor protein XB130 is a Rac-controlled component of lamellipodia that regulates cell motility and invasion

“…In search for molecular relatives of AFAP-110, we have recently cloned and begun to characterize a protein termed XB130 (also known as AFAP1L2, actin-filament-associated protein-1-like 2), which exhibits 35% sequence homology with AFAP-110 (Emaduddin et al, 2008;Xu et al, 2007). The structure of XB130 is characteristic of an adaptor protein because it contains several protein-protein and lipid-protein interaction motifs.…”