Regulation of Early Steps of GPVI Signal Transduction by Phosphatases: A Systems Biology Approach
Fig 2
A schematic diagram of the reactions captured in each of our mathematical models.
In all models GPVI, its associated Fc receptor γ-chain and Src family kinase, are treated as one unit. A ligand binds to this receptor bundle, which is subsequently phosphorylated, allowing for recruitment and activation of the cytosolic tyrosine kinase Syk. Binding to the receptor leads to auto-phosphorylation of Syk on tyrosine 525 (Y525), allowing the receptor to signal downstream. Model A incorporates a simple phosphatase that is able to dephosphorylate Syk on Y525, returning the receptor complex to an inactive state. In Model B an additional Syk phosphorylation site is incorporated (Y323), to which the newly introduced protein c-Cbl can bind. This allows Syk to set off a series of reactions, that include ubiquitination and the binding of the phosphatase TULA-2 that is able to dephosphorylate Syk on Y525, returning the receptor complex to an inactive state. In Model C two modifications are incorporated: the modification H1 allows TULA-2 to dephosphorylate not only the Syk molecule to which it is bound but also any nearby bound Syk molecule; in the second modification (H2) phosphorylation of Y525 results in an enhanced rate of Y323 phosphorylation. Model C, H3 incorporates H1 and H2 simultaneously.