Phosphatase resistance of ERK2 brain kinase PK40erk2.
We have previously shown that a brain protein kinase, termed PK40, catalyzes the multiple phosphorylation of the KSP-repeat site of neurofilaments (NFs) and also can transform tau proteins into the paired helical filament-like state as found in Alzheimer's disease (AD) brains. Protein sequence analysis suggests that PK40 is a form of the extracellular signal-regulated kinase ERK2. A subpopulation of ERK2 species in soluble brain fractions can be efficiently phosphorylated and activated in cell-free systems, simply by adding Mg(2+)-ATP. Two phosphoisoforms of PK40erk2 are formed in this process, which have a reduced gel mobility, very much like the ERK2 form obtained in cell culture by stimulation with growth factors. One of these low-mobility forms cannot be inactivated with protein phosphatase 2A (PP2A) or with tyrosine phosphatases. The second form can be slowly inactivated by PP2A. In this case two Ser/Thr phosphates are removed at different rates during inactivation: One phosphate is very quickly removed to result in the formation of a high-mobility 39-kDa ERK2 species without consequence for activity; the other, slowly removed Ser/Thr phosphate controls the activity but has no effect on the gel mobility of ERK2. These results show that forms of ERK2 exist with properties different from the previously characterized ERK2 (p42mapk) from stimulated cell cultures. The active ERK2 forms produced in the presence of Mg(2+)-ATP alone could provide an explanation for the existence of constitutive ERK2-like NF phosphorylation in vivo. Excessive formation of an ERK2 species resistant to inactivation by PP2A might be relevant to the persistent pathological tau hyperphosphorylation in AD.
Roder
H M
HM
Institute for Demetia Research, West Haven, CT 06516, USA.
Hoffman
F J
FJ
Schröder
W
W
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002417:Cattle; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D008969:Molecular Sequence Data; D010710:Phosphates / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology*; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D007527:Isoenzymes; D010710:Phosphates; D010768:Phosphoserine; D019000:Phosphotyrosine; D014443:Tyrosine; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D000469:Alkaline Phosphatase; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases