This work was supported by grants from the A. D. Williams Committee atVirginia Commonwealth University, by the Kate and Thomas Jeffress FoundationTrust, and by grant 9904765 from the National Science Foundation. The authorsare extremely grateful to J. Bradley Hullett, Abdul Rahman Kenyatta, NickyCaran, Helen Han, and Nicai Zollar for technical support, to Dr. Rita Shiangfor providing the P19 cell line, to Dr. Don Porter for assistance withsite-specific mutagenesis, and Dr. Robert J. DeLorenzo for comments on themanuscript.

  • 1
    Bain G., Ray W.J., Yao M., Gottlieb D.I. (1994) From embryonal carcinoma cells to neurons: the P19 pathway.Bioessays 16343348.
  • 2
    Bayer K.U., Harbers K., Schulman H. (1998) alphaKAP is an anchoring protein for a novel CaM kinase II isoform in skeletal muscle.EMBO J. 1755985605.
  • 3
    Bayer K.U., Löhler J., Schulman H., Harbers K. (1999) Developmental expression of the CaM kinase II isoforms: ubiquitous γ and δ-CaM kinase II are the early isoforms and most abundant in the developing nervous system. Mol. Brain Res. 70147154.
  • 4
    Braun A.P. & Schulman H. (1995) The multifunctional calcium/calmodulin-dependent protein kinase: from form to function.Annu. Rev. Physiol. 57417445.
  • 5
    Brocke L., Srinivasan M., Schulman H. (1995) Developmental and regional expression of multifunctional Ca2+/calmodulin-dependent protein kinase isoforms in rat brain. J. Neurosci. 1567976808.
  • 6
    Bystroff C. & Baker D. (1998) Prediction of local structure in proteins using a library of sequence-structure motifs.J. Mol. Biol. 281565577.
  • 7
    Dayton J.S., Sumi M., Nanthakumar N.N., Means A.R. (1997) Expression of a constitutively active Ca2+/calmodulin-dependent kinase in Aspergillus nidulans spores prevents germination and entry into the cell cycle.J. Biol. Chem. 27232233230.
  • 8
    Edman C.F. & Schulman H. (1994) Identification and characterization of δb-CaM kinase and δc-CaM kinase from rat heart, two new multifunctional Ca2+ and CaM-dependent protein kinase isoforms.Biochim. Biophys. Acta 122189101.
  • 9
    Hall A. (1998) Rho GTPases and the actin cytoskeleton.Science 279509514.
  • 10
    Hanson P.I., Meyer T., Stryer L., Schulman H. (1994) Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals.Neuron 12943956.
  • 11
    Karls U., Müller U., Gilbert D.J., Copeland N.G., Jenkins N.A., Harbers K. (1992) Structure, expression, and chromosome location of the gene for the β subunit of brain-specific Ca2+/calmodulin-dependent protein kinase II identified by transgene integration in an embryonic lethal mouse mutant. Mol. Cell. Biol. 1236443652.
  • 12
    Kelly P.T. (1991) Calmodulin-dependent protein kinase II. Multifunctional roles in neuronal differentiation and synaptic plasticity.Mol. Neurobiol. 5153177.
  • 13
    Kolb S.J., Hudmon A., Ginsberg T.R., Waxham N. (1998) Identification of domains essential for the assembly of calcium/calmodulin-dependent protein kinase II.J. Biol. Chem. 2733155531564.
  • 14
    Kwiatkowski A.P. & McGill J.M. (1995) Human biliary epithelial cell line Mz-ChA-1 expresses new isoforms of calmodulin-dependent protein kinase II.Gastroenterology 10913161323.
  • 15
    Laferrière N.B. & Brown D.L. (1996) Expression and posttranslational modification of class III β-tubulin during neuronal differentiation of P19 embryonal carcinoma cells. Cell. Motil. Cytoskel. 35188199.
  • 16
    Lau P.M., Zucker R.S., Bentley D. (1999) Induction of filopodia by direct local elevation of intracellular calcium ion concentration.J. Cell Biol. 14512651276.
  • 17
    MacNicol M.C., Jefferson A.B., Schulman H. (1990) Ca2+/calmodulin kinase is activated by the phosphatidyl-inositol signaling pathway and becomes Ca2+-independent in PC12 cells. J. Biol. Chem. 2651805518058.
  • 18
    Maletic-Savatic M., Malinow R., Svoboda K. (1999) Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity.Science 28319231927.
  • 19
    Massé T. & Kelly P.T. (1997) Overexpression of Ca2+/calmodulin-dependent protein kinase II in PC12 alters cell growth, morphology, and nerve growth factor-induced differentiation. J. Neurosci. 17924931.
  • 20
    Mayer P., Möhlig M., Schatz H., Pfeiffer A. (1993) New isoforms of multifunctional Ca2+/calmodulin-dependent protein kinase II. FEBS Lett. 333315318.
  • 21
    Morris T.A., DeLorenzo R.J., Tombes R.M. (1998) CaMK-II inhibition reduces cyclin D1 levels and enhances the association of p27kip1 with cdk2 to cause G1 arrest in NIH 3T3 cells.Exp. Cell Res. 240218227.
  • 22
    Nghiem P., Saati S.M., Martens C.L., Gardner P., Schulman H. (1993) Cloning and analysis of two new isoforms of multifunctional Ca2+/calmodulin-dependent protein kinase: expression in multiple human tissues. J. Biol. Chem. 26854715479.
  • 23
    Nomura T., Kumatoriya K., Yoshimura Y., Yamauchi T. (1997) Overexpression of α and β isoforms of Ca2+/calmodulin-dependent protein kinase II in neuroblastoma cells—H-7 promotes neurite outgrowth. Brain Res. 766129141.
  • 24
    Planas-Silva M.D. & Means A. (1992) Expression of a constitutive form of calcium/calmodulin dependent protein kinase II leads to arrest of the cell cycle in G2.EMBO J. 11507517.
  • 25
    Rasmussen C. & Rasmussen G. (1994) Inhibition of G2/M progression in Schizosaccharomyces pombe by a mutant calmodulin kinase II with constitutive activity.Mol. Biol. Cell 5785795.
  • 26
    Scholz W.K., Baitinger C., Schulman H., Kelly P.T. (1988) Developmental changes in Ca2+/calmodulin-dependent protein kinase II in cultures of hippocampal pyramidal neurons and astrocytes. J. Neurosci. 810391051.
  • 27
    Schworer C.M., Rothblum L.I., Thekkumkara T.J., Singer H.A. (1993) Identification of novel isoforms of the δ subunit of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 2681444314449.
  • 28
    Shen K., Teruel M.N., Subramanian K., Meyer T. (1998) CaMKII β functions as an F-actin targeting module that localizes CaMKIIα/β heterooligomers to dendritic spines.Neuron 21593606.
  • 29
    Singer H.A., Benscoter H.A., Schworer C.M. (1997) Novel Ca2+/calmodulin-dependent protein kinase II γ-subunit variants expressed in vascular smooth muscle, brain and cardiomyocytes. J. Biol. Chem. 27293939400.
  • 30
    Solem M., McMahon T., Messing R.O. (1995) Depolarization-induced neurite outgrowth in PC12 cells requires permissive, low level NGF receptor stimulation and activation of calcium/calmodulin-dependent protein kinase.J. Neurosci. 1559665975.
  • 31
    Srinivasan M., Edman C.F., Schulman H. (1994) Alternative splicing introduces a nuclear localization signal that targets multifunctional CaM kinase to the nucleus.J. Cell Biol. 126839852.
  • 32
    Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. (1988) SRα promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat.Mol. Cell. Biol. 8466472.
  • 33
    Tashima K., Yamamoto H., Setoyama C., Ono T., Miyamoto E. (1996) Overexpression of Ca2+/calmodulin-dependent protein kinase II inhibits neurite outgrowth of PC12 cells. J. Neurochem. 665764.
  • 34
    Tobimatsu T. & Fujisawa H. (1989) Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs.J. Biol. Chem. 2641790717912.
  • 35
    Tombes R.M. & Krystal G.W. (1997) Identification of novel human tumor cell-specific CaMK-II variants.Biochim. Biophys. Acta 1355281292.
  • 36
    Tombes R.M., Auer K.L., Mikkelsen R., Valerie K., Wymann M.P., Marshall C.J., McMahon M., Dent P. (1998) The mitogenactivated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic.Biochem. J. 33014511460.
  • 37
    Tombes R.M., Mikkelsen R.B., Jarvis W.D., Grant S. (1999) Down regulation of delta CaM kinase II in human tumor cells.Biochim. Biophys. Acta 1452111.
  • 38
    Urquidi V. & Ashcroft S.J.H. (1995) A novel pancreatic β-cell isoform of calcium/calmodulin-dependent protein kinase II (β3 isoform) contains a proline-rich tandem repeat in the association domain.FEBS Lett. 3582326.
  • 39
    VanBerkum M.F. & Goodman C.S. (1995) Targeted disruption of Ca(2+)-calmodulin signaling in Drosophila growth cones leads to stalls in axon extension and errors in axon guidance.Neuron 144356.
  • 40
    Waldmann R., Hanson P.I., Schulman H. (1990) Multifunctional Ca2+/calmodulin-dependent protein kinase made Ca2+-independent for functional studies. Biochemistry 2916791684.
  • 41
    Wang H.Y., Goligorsky M.S., Malbon C.C. (1997) Temporal activation of Ca2+/calmodulin-sensitive protein kinase type II is obligate for adipogenesis. J. Biol. Chem. 27218171821.
  • 42
    Watanabe Y., Watanabe T., Kitigawa M., Taya Y., Nakayama K., Motoyama N. (1999) pRb phosphorylation is regulated differentially by cyclin-dependent kinase (Cdk)2 and Cdk4 in retinoic acid-induced neuronal differentiation of P19 cells.Brain Res. 842342350.
  • 43
    Williams E.J., Mittal B., Walsh F.S., Doherty P. (1995) A Ca2+/calmodulin kinase inhibitor, KN-62, inhibits neurite outgrowth stimulated by CAMs and FGF. Mol. Cell. Neurosci. 66979.
  • 44
    Wu G.Y. & Cline H.T. (1998) Stabilization of dendritic arbor structure in vivo by CaMKII.Science 279222226.