Recently, monocytes expressing the TIE-2/tek receptor tyrosine kinase (TEM: TIE-2 expressing monocytes) have been identified in peripheral blood and tumors of humans and mouse [34,35].

While we have previously reported that TIE-2 and VEGFR kinase

The first group of treatments combined TIE-2 tyrosine kinase inhibitor with TGF-B and a ligand of VEGFR-l or TIE-2.

Treatments from the second group involved VEGFR-l kinase inhibitor, and the third group of treatments associated TGF-B with TNF-oc and a ligand of TIE-2 or VEGFR-l (Table 4).

With currently available tools, VEGFR-l kinase activity is almost impossible to manipulate.

Tumor TEM were exposed to TIE-2 kinase inhibitor combined with TGF-B and simultaneously engaged their VEGFR-l using VEGF (alternatively PlGF, Table 4 and Fig.

For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer.

The EGF receptor is a flexible protein with four distinct domains, including extracellular and transmembrane regions, the intracellular kinase domains, and a long flexible tail (Fig.

Mutations in the extracellular region of EGF receptor have been associated with ligand-independent dimerization in cancers of the central nervous system[46] , and mutations in the intracellular region of EGF receptor are associated with sensitivity to kinase inhibitors[46].

In lung cancers, mutations were significantly enriched in the tyrosine kinase domain (Pki-nase_Tyr).

These five interaction-mediating domain pairs are Bcl-2 and BH4 domains encoded by BCL2, which play important roles in regulating cell death and survival[65]; DEAD and Helicase_C domains encoded by DDX3X, which play important roles in metabolic processes involving RNAs[66]; and PI3Ka and P13K_p85B domains encoded by PIK3CA, which interact with each other to initiate a vast array of signaling events[67]; Furin-like and GF_recep_IV domains encoded by EGFR, which are both extracellular domains of receptor tyrosine protein kinases and which interact with each other to regulate the binding of ligands to the receptor[68]; and finally the DNA binding and P53_tetramer (tetrameriza-tion) domains encoded by TP53.

For each cancer type, we found at least one new potential cancer-associated domain instance, for example, the diacylglycerol kinase domain encoded by DGKZ in chondrosarcoma.

For example, it was reported that 80% of non-synonymous single-base substitutions observed in genes encoding protein kinases are passenger mutations [24].

Similarly, the effects of mutations in different protein kinase sub-domains have been shown to have different functional impacts[28].

Consistent with this view, we found a single hotspot (p. N549) for FGFR2 in breast cancer in the kinase domain, which had not been reported as a hot-spot for breast cancer.

Supporting this view, we observed nine evenly-distributed mutated residues in the kinase domain in endometrial cancer, although we also confirm previous observation [54] of the p.N549 hotspot which is more suggestive of an oncoprotein.

They are V600 in Serine/threonine-protein kinase B-Raf (encoded by BRAF), and R88 and C420 in the phos-phatidylinositol-4,5-bisphosphate 3-kinase encoded by PIK3CA.

Specifically it is known to inhibit Raf kinases, Receptor-type ty-rosine-protein kinase (FLT3), platelet-derived growth factor (PDGF), Vascular endothelial growth factor receptor 2 & 3 (VEGF2/ 3) and the Mast/stem cell growth factor receptor Kit.

However, there are two links not annotated within the predictions, the serine/threonine-protein ki-nase A-Raf (ARAF) and the Cyclin-dependent kinase 10 (CDKIO).

Regarding the Cyclin dependent kinases CDK10 and CDK19 proposed binding sites, CDK10 binding site has a high similarity (ProBiS Z-score of 2.09) with the MAPK14 ’s one while the CDK19 binding site is almost identical to that of CDK8 (ProBiS 2.9).