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

abstract: ...Background Src 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. Results 64 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. Conclusion Rapid 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.

...Cell Commun Signal Cell Communication and Signaling : CCS 1478-811X BioMed Central 18844995 2584000 1478-811X-6-7 10.1186/1478-811X-6-7 Research Odin (ANKS1A) is a Src family kinase target in colorectal cancer cells Emaduddin Muhammad 1 muhammad.emaduddin@imm.ox.ac.uk Edelmann Mariola J 2 mariola.edelmann@jesus.ox.ac.uk Kessler Benedikt M 2 bmk@ccmp.ox.ac.uk Feller Stephan M 1 cellsignal@imm.ox.ac.uk 1 Cell Signalling Group, Department of Molecular Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, Headley Way, Oxford OX3 9DS, UK 2 Central Proteomics Facility (CPF), Henry Wellcome Building for Molecular Physiology, Department of Clinical Medicine and Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, Headley Way, Oxford OX39DS, UK 2008 9 10 2008 6 7 7 16 8 2008 9 10 2008 Copyright 2008 Emaduddin et al; licensee BioMed Central Ltd. 2008 Emaduddin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background Src 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. Results 64 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. Conclusion Rapid 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. Background Src family

.... The AceView program predicts numerous putative isoforms for cortactin, but the splice-variants occurring in colonic epithelium or colorectal cancers have not yet been reported. Other known SFK substrates identified were vimentin [ 11 , 12 ], 3BP-2 (SH3BP2) [ 13 ], GIT1 [ 14 ], Tom1L1 [ 15 ] and AFAP1L2/XB130 [ 16 ]. The adaptor protein CRKL, the major target of the Bcr-Abl oncogene [ 17 ], a tyrosine kinase activating SFK in CML cells, was also detected. Other proteins found by MS, for example

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Gene: AFAP1L2 - actin filament associated protein 1-like 2 - (NCBI)

Protein : 2cof

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