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Published online January 2, 2007
doi:10.1083/jcb.200607128
The Journal of Cell Biology, Vol. 176, No. 1, 101-111
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Han et al.
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Article

 Spatial targeting of type II protein kinase A to filopodia mediates the regulation of growth cone guidance by cAMP

Jianzhong Han, Liang Han, Priyanka Tiwari, Zhexing Wen, and James Q. Zheng

Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854

Correspondence to James Q. Zheng: zhengjq{at}umdnj.edu

The second messenger cyclic adenosine monophosphate (cAMP) plays a pivotal role in axonal growth and guidance, but its downstream mechanisms remain elusive. In this study, we report that type II protein kinase A (PKA) is highly enriched in growth cone filopodia, and this spatial localization enables the coupling of cAMP signaling to its specific effectors to regulate guidance responses. Disrupting the localization of PKA to filopodia impairs cAMP-mediated growth cone attraction and prevents the switching of repulsive responses to attraction by elevated cAMP. Our data further show that PKA targets protein phosphatase-1 (PP1) through the phosphorylation of a regulatory protein inhibitor-1 (I-1) to promote growth cone attraction. Finally, we find that I-1 and PP1 mediate growth cone repulsion induced by myelin-associated glycoprotein. These findings demonstrate that the spatial localization of type II PKA to growth cone filopodia plays an important role in the regulation of growth cone motility and guidance by cAMP.

Abbreviations used in this paper: AKAP, a kinase-anchoring protein; BDNF, brain-derived neurotrophic factor; CaMKII, Ca-calmodulin–dependent kinase II; CaN, calcineurin; CM, control morpholino; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of 32 kD; I-1, inhibitor-1; IM, I-1 morpholino; IP, immunoprecipitation; MAG, myelin-associated glycoprotein; NT-3, neurotrophin-3; OA, okadaic acid; PACAP, pituitary adenylate cyclase–activating polypeptide; PP1, protein phosphatase-1.


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