Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo.
Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor purvalanol decreases the phosphorylation of CRMP proteins in neurons, whereas CRMP1 and CRMP2, but not CRMP4, phosphorylation is decreased in Cdk5(-/-) cortices. Stimulation of neuroblastoma cells with IGF1 or TPA decreases GSK3 activity concomitantly with CRMP2 and CRMP4 phosphorylation. Conversely, increased GSK3 activity is not sufficient to increase CRMP phosphorylation. However, the growth cone collapse-inducing protein Sema3A increases Cdk5 activity and promotes phosphorylation of CRMP2 (but not CRMP4). Therefore, inhibition of GSK3 alters phosphorylation of all CRMP isoforms; however, individual isoforms can be differentially regulated by their respective priming kinase. This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease.
Cole
Adam R
AR
Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland.
Causeret
Frédéric
F
Yadirgi
Gokhan
G
Hastie
C James
CJ
McLauchlan
Hilary
H
McManus
Edward J
EJ
Hernández
Félix
F
Eickholt
Britta J
BJ
Nikolic
Margareta
M
Sutherland
Calum
C
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D040121:Semaphorin-3A / Q000378:metabolism / Q000502:physiology*; D000098855:Collapsin Response Mediator Protein 1
D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D036341:Intercellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D040121:Semaphorin-3A; C102924:CRMP1 protein, human; D000098855:Collapsin Response Mediator Protein 1; C102926:DPYSL3 protein, human; C449760:Dpysl3 protein, rat; C095114:collapsin response mediator protein-2