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The Journal of Neuroscience, May 5, 2004, 24(18):4421-4431; doi:10.1523/JNEUROSCI.0690-04.2004

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Cellular/Molecular
p35/Cyclin-Dependent Kinase 5 Phosphorylation of Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2) Mediates Rac-Dependent Extracellular Signal-Regulated Kinase 1/2 Activity, Altering RasGRF2 and Microtubule-Associated Protein 1b Distribution in Neurons

Sashi Kesavapany,^1 * Niranjana Amin,^1 * Ya-Li Zheng,¹ Ruchika Nijhara,³ Howard Jaffe,² Ram Sihag,¹ J. Silvio Gutkind,⁴ Satoru Takahashi,⁵ Ashok Kulkarni,⁵ Philip Grant,¹ and Harish C. Pant¹

¹Laboratory of Neurochemistry and ²Protein and Peptide Facility, National Institute of Neurological Disorders and Stroke, ³Laboratory of Molecular Immunology, National Cancer Institute, ⁴Oral and Pharyngeal Cancer Branch, ⁵Functional Genomics Unit, National Institute of Dental and Cranofacial Research, National Institutes of Health, Bethesda, Maryland 20892

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase the activity of which is dependent on association with its neuron-specific activators, p35 and p39. Cdk5 activity is critical for the proper formation of cortical structures and lamination during development. In the adult nervous system, Cdk5 function is implicated in cellular adhesion, dopamine signaling, neurotransmitter release, and synaptic activity. In addition, Cdk5 is also involved in "cross-talk" with other signal transduction pathways. To further examine its involvement in cross-talk with other pathways, we identified proteins that interacted with p35 using the yeast two-hybrid system. We report here that p35 associates with Ras guanine nucleotide releasing factor 2 (RasGRF2) in coimmunoprecipitation and colocalization studies using transfected cell lines as well as primary cortical neurons. Additionally, Cdk5 phosphorylates RasGRF2 both in vitro and in vivo, leading to a decrease in Rac–guanidine exchange factor activity and a subsequent reduction in extracellular signal-regulated kinase 1/2 activity. We show that p35/Cdk5 phosphorylates RasGRF2 on serine⁷³⁷, which leads to an accumulation of RasGRF2 in the neuronal cell bodies coinciding with an accumulation of microtubule-associated protein 1b. The membrane association of p35 and subsequent localization of Cdk5 activity toward RasGRF2 and Rac provide insights into important cellular signaling processes that occur at the membrane, resulting in downstream effects on signal transduction cascades.

Key words: p35/Cdk5; RasGRF2; phosphorylation; Rac; ERK1/2; MAP1b

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Received Dec 29, 2003; revised March 29, 2004; accepted March 30, 2004.

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