Fig. 4.

Kinase activity analysis reveals active kinases, kinase superfamilies, and AKT substrates in HGGs. a Hierarchical clustering analysis of reprogrammed kinase activities, which were derived from substrate phosphorylation in the HGG tumors via the IKAP algorithm. The hierarchical clustering was performed by WARD’s method. Activity patterns of protein clusters were compared with the phosphoproteome expression patterns in Fig. 3c. Patterns that match the clusters in Fig. 3c were labeled on the right side of the panel. For instance, cluster on the most upper side shows an activity pattern of NTRK > PDGDFRA > Cortex, similar to the phosphoproteome pattern 2 (PP-C2 pattern) in Fig. 3c. Color key represents the Z score of substrate-derived activities. b Construction of a putative core kinase-to-kinase signaling network with consistent co-activation patterns across different samples. To construct a putative kinase centered signaling network in HGG, we incorporated the relationships of kinase-substrate from PhosphoSitePlus, and manually accepted kinase−kinase networks with consistent coactivation patterns across different samples. Solid black arrows represent direct activation through phosphorylation and dotted black arrows represent indirect connection between upper kinase and downstream kinase. c Summarization of individual kinase activity into kinase superfamily shows stronger rewiring of AGC and CMGC superfamilies in the NTRK HGG than the PDGFRA HGG. Kinome tree map shows pairwise kinase activity comparisons, in which the kinase superfamilies with statistically significant difference are shown with p values determined by chi-square. Kinase activity levels are represented by the length of bars outside of the kinome tree circle. d Putative substrates activated by AKT, the central hub of PI3K-AKT cascades in HGGs. AKT-regulated substrates and their phosphosites are organized by annotated functions. Biological function groups are presented by distinct colors. The distance between substrates and the AKT center is correlated with substrate phosphorylation level. e.g. AMPKA1 is one of the AKT substrates with the highest phosphorylation level. HGG high-grade glioma