Development - Role of CDK5 in neuronal development

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Role of CDK5 in neuronal development

Cyclin-dependent kinase 5 (CDK5) is a member of the small serine/threonine cyclin-dependent kinase (CDK) family.

One of the important roles of CDK5 is a neuronal development and differentiation. There are several activators of CDK5. Role of Neuronspecific activator, cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1(p35)) in neuron development and differentiation is most well-known [1].

CDK5R1(p35)/ CDK5 controls axonal transport of organelles and proteins (both axonal and anterograde).

One of the most well-known pathways is the CDK5 regulation of Reelin signaling. Reelin is a large secreted signaling glycoprotein that binds to two members of the Low-density lipoprotein receptor family, the Apolipoprotein E receptor-2 (ApoER2) and the Very-low-density lipoprotein receptor (VLDLR). Reelin-activated ApoER2 and VLDLR activate Disabled-1 (Dab1) [2]. It is believed that Dab1 induces protein-tyrosine kinase Fyn activation and is phosphorylated in return [3]. Then, Fyn-phosphorylated Dab1 activatesPhosphoinositide-3-kinase (PI3K)/ v-akt murine thymoma viral oncogene homolog 1 (AKT)/ Glycogen synthase kinase 3 beta (GSK3 beta) pathway [4]. It is known that GSK3 beta is implicated in the regulation of anterograde axonal transport, possibly via phosphorylation of Microtubule-associated protein tau (Tau (MAPT)) [5]. CDK5R1(p35)/ CDK5 inhibited this pathway via phosphorylation of Dab1 [2], [4].

In addition, it is shown that CDK5R1(p35)/ CDK5 phosphorylates Thiol-activated peptidase (NUDEL). NUDEL, along withPlatelet-activating factor acetylhydrolase, isoform Ib alpha subunit (PAFAH1B1(LIS1)), interacts with Dynein 1, cytoplasmic, heavy chain, and thus regulates axonal retrograde transport [6], [7].

Moreover, it is known that CDK5R1(p35)/ CDK5 may regulate neurofilament transport via phosphorylation of Neurofilament H (NEFH), Neurofilament M (NEFM) and Neurofilament L (NEFL) [8], [9] that all are bound to Dynein/ Dynactin motor complex [10], [11].

It is shown that phosphorylation of the neurofilaments by CDK5R1(p35)/ CDK5 can also regulate neurite outgrowth and axon radial growth [8], [12].

CDK5R1(p35)/ CDK5 regulates formation of dendrites during neuronal development. CDK5R1(p35)/ CDK5 directly phosphorylates Beta-catenin and Delta-catenin at Ser-246. Phosphorylated catenins may interact with Protein NIMA-interacting 1 (Pin1) that inhibits catenin degradation [13]. It leads to stimulation of dendrites formation.

On the other hand, CDK5R1(p35)/ CDK5 phosphorylates the Wiskott-Aldrich syndrome protein (WASP)-family veroroline homologous protein 1 (WASF1(WAVE1)). Phosphorylation of WASF1(WAVE1) inhibits its ability to regulate Arp2/3 complex-dependent Actin polymerization and decrease the number of spines on the mature dendrites [14].


  1. Dhavan R, Tsai LH
    A decade of CDK5. Nature reviews. Molecular cell biology 2001 Oct;2(10):749-59
  2. Tissir F, Goffinet AM
    Reelin and brain development. Nature reviews. Neuroscience 2003 Jun;4(6):496-505
  3. Arnaud L, Ballif BA, Förster E, Cooper JA
    Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Current biology : CB 2003 Jan 8;13(1):9-17
  4. Bock HH, Jossin Y, Liu P, Förster E, May P, Goffinet AM, Herz J
    Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. The Journal of biological chemistry 2003 Oct 3;278(40):38772-9
  5. Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I
    Role of tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport. Journal of cell science 2004 Apr 1;117(Pt 9):1653-63
  6. Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J, Wynshaw-Boris A, Hirotsune S
    A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 2000 Dec;28(3):681-96
  7. Niethammer M, Smith DS, Ayala R, Peng J, Ko J, Lee MS, Morabito M, Tsai LH
    NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 2000 Dec;28(3):697-711
  8. Grant P, Sharma P, Pant HC
    Cyclin-dependent protein kinase 5 (Cdk5) and the regulation of neurofilament metabolism. European journal of biochemistry / FEBS 2001 Mar;268(6):1534-46
  9. Ackerley S, Thornhill P, Grierson AJ, Brownlees J, Anderton BH, Leigh PN, Shaw CE, Miller CC
    Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments. The Journal of cell biology 2003 May 12;161(3):489-95
  10. Shah JV, Flanagan LA, Janmey PA, Leterrier JF
    Bidirectional translocation of neurofilaments along microtubules mediated in part by dynein/dynactin. Molecular biology of the cell 2000 Oct;11(10):3495-508
  11. Motil J, Chan WK, Dubey M, Chaudhury P, Pimenta A, Chylinski TM, Ortiz DT, Shea TB
    Dynein mediates retrograde neurofilament transport within axons and anterograde delivery of NFs from perikarya into axons: regulation by multiple phosphorylation events. Cell motility and the cytoskeleton 2006 May;63(5):266-86
  12. Sharma M, Sharma P, Pant HC
    CDK-5-mediated neurofilament phosphorylation in SHSY5Y human neuroblastoma cells. Journal of neurochemistry 1999 Jul;73(1):79-86
  13. Muñoz JP, Huichalaf CH, Orellana D, Maccioni RB
    cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal cells. Journal of cellular biochemistry 2007 Feb 15;100(3):738-49
  14. Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, Halford JM, Kim AM, Kwak SP, Park JB, Ho Ryu S, Schenck A, Bardoni B, Scott JD, Nairn AC, Greengard P
    Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 2006 Aug 17;442(7104):814-7

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