In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endo-somes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half ofthe receptortyrosine kinases in the human genome.

The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases , especially FYN and LYN.

We found that two related proteins (FYN and LYN) act like central hubs in the tyrosine kinase signaling network that change intracellular localization and activity in response to activation of different receptors.

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase (RTK), is frequently mutated and activated in both familial and spontaneous neuroblastomas, suggesting that this receptor can prevent a key differentiation step in neural crest cells [9—15].

Tyrosine kinase signaling networks play a major role in governing cell differentiation, including in neuroblastoma [16].

There are 90 tyrosine kinases in the human genome; 58 of these are receptor tyrosine ki-nases [17,18] , many of which have unknown functions.

Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinosi-tide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration.

The applied MEK inhibitor, for example, blocks MEK kinase activity, thus inhibiting the outgoing edges from MEK.

Upon binding to its receptor Met, HGF activates the phosphoinositide-(PI)-3-kinase (PI3K) and the mitogen activated protein kinase (MAPK) signaling pathways.

In general, activation of PI3K leads to the generation of phosphatidylinositol 3,4,5—triphos-phate (PI3,4,5-P3) that serves as docking site for the serine/threonine protein kinase Akt at the plasma membrane.

Activated Raf leads to phosphorylation of a dual specific kinase, the mitogen-activated protein kinase kinase (MEKI and 2), that phosphorylates the extracellular-signal regulated kinase (ERK1 and 2).

The activation of GPVI (the only non-GPCR receptor targeted in our study) by Collagen or CRP leads to Lyn and Fyn phosphorylation of the FcR gamma-chain[23] , allowing Syk docking[24] and activation of phospholipase C (PLC)y2 [25] and Phosphoinositide 3 kinase (PISK) [26,27].

We investigated reagents thought to act primarily on siX proteins in pathways of major thera-Epinephrine Receptor (E), P13 Kinase (P), and GPVI Collagen Receptor (C).

There was no inhibitor available for GPVI, and an inhibitor of PI3 kinase was included because of its inhibitory effects on GPVI stimulated activation.

Drugs have been developed to target the IGFIR pathway by suppressing the IGFI to HIFloc pathway using three main types of compounds: IGFIR targeting antibodies, tyrosine kinase inhibitors for kinase domains of IGFIR, and IGFI ligand neutralizing antibodies [24, 77—79].

This explains why when U87 and LN229 were targeted using TAE226 (IGFIR tyrosine kinase inhibitor), a larger amount of apoptosis was observed for the LN229 cell line compared to the U87 cells [3].

IGFBP2 was previously shown to interact with integrin alpha 5 [65] , which further signals to Integrin Linked Kinase (ILK).

SBF/MBF activity is controlled by the G1 network, which involves the cyclin dependent kinase (CDK) Cdc28, its activating subunits the G1 cyclins Cln1/2/3 and the transcriptional repressor Whi5 (reviewed in [3]).

The kinase responsible for mitotic entry Clb2-Cdc28 is inhibited through phosphorylation at the Tyr19 residue by Swe1

Finally, we simplify phase transitions to a threshold for nuclear kinase activity, assuming zero order ultra-sensitivity [60].