Fig. 4: Focal adhesion signalling in pre-metastatic disease progression. | npj Precision Oncology

Fig. 4: Focal adhesion signalling in pre-metastatic disease progression.

From: Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary Thyroid Cancer

Fig. 4

a Altered kinase signatures for M918T carriers identified within the PamGene kinome array, along with their putative upstream kinases, were mapped to KEGG pathway networks comprising adherens junction (pink), focal adhesion (green) and non-canonical Wnt signalling (blue) modules. b Phosphorylation state of components of the focal adhesion pathway: Insulin receptor tyrosine kinase alpha subunit (INSR), Insulin receptor substrate 2 (IRS2) and Eph receptor tyrosine kinase A2 (EPHA2), identified by PamChip microarrays. INSR was analysed by One-way ANOVA followed by Brown-Forsythe test. IRS2 analysed by Kruskal-Wallis test. EPHA2 was analysed by Brown-Forsythe and Welch ANOVA. * p < 0.05. Phospho-sites located within each peptide are shown underneath (circles show threonine, white triangles show serine, black triangles show tyrosine residues. c Heatmap of the Z-scored differential activity of all kinases within the KEGG pathways shown in (a). d Immunohistochemistry H-DAB staining of patient thyroid tissue, probed for either β-catenin or GSK3β. The tissues are labelled with the pathogenic variant, patient participant number and the total sample number for that pathogenic variant. For each β-catenin and GSK3β, the scale bar for the images on the left represents 500 µm, with the hashed box showing the location of the closer in image on the right. For images on the right the scale bar represents 100 µm. Quantification of cellular e β-catenin and f GSK3β levels within patient tissues. Left, data is organised by each pathogenic variant, with colours representing the histology type (group 1 (Histologically normal) orange, group 2 (CCH) pink, group 3 (MTC) blue, group 4 (m-MTC) green). In the right graph data is organised by histology type, with colours representing the corresponding pathogenic variant (C609x-C634x green, S891A orange, V804M blue, M918T purple). Analysed by One-way ANOVA followed by Brown-Forsythe test, * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. For β-catenin; C609x-C634x n = 14, S891A n = 9, V804M n = 11, M918T n = 10: Group 1 (histologically normal) n = 4, group 2 (CCH) n = 15, group 3 (MTC) n = 10, group 4 (m-MTC) n = 15). For GSK3β; C609x-C634x n = 16, S891A n = 2, V804M n = 11, M918T n = 13: Group 1 (histologically normal) n = 4, group 2 (CCH) n = 10, group 3 (MTC) n = 13, group 4 (m-MTC) n = 15. g The calculated change in kinetic effect of the PIM1, PIM2, CK1α and GSK3β kinases for each MEN2 pathogenic variant group. h Heatmap of the Z-scored differential activity of kinases within the focal adhesion pathway.

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