Glycogen synthase kinase three four is an evolutionarily conserved and ubiquitously expressed Ser/Thr kinase that’s expressed as two closely related isoforms in mammals, GSK3 and GSK3. GSK3 is uncommon when compared with other protein kinases since it is constitutively active in cells and phosphorylation of most substrates should be preceded by phosphorylation of a nearby residue by a different kinase. This course of action is known as priming and happens at Ser/Thr residues situated four or five residues C terminal towards the web page Serotonin phosphorylated by GSK3. GSK3 activity is inhibited by phosphorylation of an N terminal serine residue, which is catalyzed by members from the AGC loved ones of protein kinases upon stimulation by growth elements. Alternatively, GSK3 activity might be inhibited by protein protein interactions following activation on the Wnt signaling pathway. It’s also doable that regulation of priming kinases could indirectly regulate phosphorylation of substrates by GSK3, though this has yet to be proven. We’ve lately found new brain precise substrates for GSK3, namely collapsin response mediator protein two and four. These isoforms are members of a household of 5 CRMP proteins which can be expressed just about ubiquitously throughout the central nervous method.
CRMP2 could be the most effective studied isoform of the family members. Mammalian CRMP2 binds to tubulin heterodimers to promote microtubule formation and co localizes with microtubules inside cells.
Overexpression of CRMP2 in hippocampal neurons promotes increased axon elongation. Even so, mutation of the GSK3 phosphorylation web sites on CRMP2 to non phosphorylatable alanine residues Neu receptor alters CRMP2 induced axon elongation. Other functions attributed to CRMP2 involve regulation of cell surface receptor internalization, Semaphorin induced growth cone collapse and axonal transport. Importantly, hyperphosphorylated CRMP2 has been detected inside neurofibriliary tangles in the brains of Alzheimer,s illness individuals and the residues hyperphosphorylated match these phosphorylated by GSK3. In contrast to CRMP2, somewhat little is identified about the function on the other CRMP isoforms. Human CRMP1 four are ?572 amino acids in length, 62 kDa in size and share a higher amount of sequence homology, whereas CRMP5 is more divergent. All CRMP isoforms are members on the amidohydrolase family members of structural proteins, although they do not possess any amidohydrolase enzymatic activity. The residues in CRMP2 phosphorylated by GSK3 too because the priming website are conserved in human CRMP1 and CRMP4, but not in CRMP3 or CRMP5. Even though CRMP2 and CRMP4 have been identified as GSK3 substrates, the status of CRMP1 regulation by phosphorylation is at the moment unknown. It has not too long ago been shown that Cdk5 can phosphorylate Ser522 of CRMP2.