| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
|
|---|
| Research Abstract |
Mitogen-activated protein kinases (MAPKs) are inactivated through dephosphorylation of regulatory Tyr and Thr residues by phosphatases. Recently we have found that mammalian MAPKs including ERK are dephosphorylated and inactivated by tyrosine-specific phosphatases, such as LC-PTP, PTPBR7, and STEP.Among these phosphatases, LC-PTP is predominantly expressed in hematopoietic cells and thus, it might be involved in the novel regulation system of MAPK in lymphocytes.
First, we found the complex formation of LC-PTP and MAPK.Then, we identified the binding site in LC-PTP.A short stretch of amino acids outside the phosphatase domain of LC-PTP is essential and enough for the MAPK binding activity. It is also essential for the MAPK inhibition.
The binding site in ERK and p38 MAPK was also identified. Drosophila sevenmaker (sem) mutant is a gain-of-function mutant that is caused by a point mutation of an Asp residue in MAPK.The corresponding mutation was introduced into mammalian ERK and p38 MAPKs. Wild type MAPKs but not these sem MAPKs associated with LC-PTP, indicating that the residue was critically involved in the association. More importantly, sem MAPKs were resistant to the suppression by LC-PTP and hyperactive in vivo.
Thus, the association of MAPK with phosphatases is crucial for its regulation. The sem MAPKs might be useful probes to elucidate the physiological function of the phosphatases.
|
