Kinase pathway elucidation

Activation of the enzyme PIS kinase (PI3K) constitutes a third pathway of Trk receptor signaling. The precise mechanism by which PI3K activation occurs has not yet been completely elucidated, but appears to involve Trk activation of intermediate proteins, such as insulin receptor substrate (IRS)-1,2 and the IRS-like protein Gabl. Downstream of PI3K activation is stimulation of the kinase Akt, which is largely responsible for the survival effects mediated by this pathway. 

In 1966 Fischer and Krebs published their seminal work on protein phosphorylation and its regulatory function in cellular pathways.1 Since then, great strides have been made in our understanding of protein kinases, their functional roles in cellular processes, and their pathogenic roles in diseases. Bishop and Varmus received the 1989 Nobel Prize for their work on oncogenic kinases.2 In 2001, Nurse and Hunt were also awarded the Nobel Prize for their work in elucidating the role of cyclins and cyclin-dependent kinases in regulating cell cycles.3... 

There are numerous data that peroxynitrite is involved in cell death and tissue injuries in many clinical conditions. An important mechanism underlying peroxynitrite toxicity is the reaction of tyrosine nitration. Tyrosine nitration inactivates certain enzymes, as was postulated for prostacyclin (PGI2) synthase (M14), cytochrome P450 2B1 (RIO), tyrosine hydroxylase (A 14), and MnSOD (Yl). Moreover, nitration blocks tyrosine phosphorylation, and thus interferes with the tyrosine kinase signaling pathways (K18). The peroxynitrite treatment of rat liver epithelial cells stimulates mitogen-activated protein kinases p38 MAPK, JNK1/2, and ERK1/2 the mechanism of this effect awaits elucidation (S9). 

Several inhibitors of upstream kinases Raf and MEKl/2 are used widely in elucidating the physiologic roles of the ERK pathways in a variety of biologic processes in cell culture systems (Figs. 1 and 2) (12, 13). The MEKl/2 inhibitors U0126, PD98059, and PD184352 (IC-1040) are noncompetitive with respect to both MEK substrates, ATP and ERKl/2, which is... 

---