Spatial targeting of type II protein kinase A to filopodia mediates the regulation of growth cone guidance by cAMP.
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.
Han
Jianzhong
J
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
Han
Liang
L
Tiwari
Priyanka
P
Wen
Zhexing
Z
Zheng
James Q
JQ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D020439:Growth Cones / Q000187:drug effects*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D018992:Myelin-Associated Glycoprotein / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects* / Q000201:enzymology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014981:Xenopus
D008869:Microtubule-Associated Proteins; D018992:Myelin-Associated Glycoprotein; D011506:Proteins; C073882:phosphoprotein phosphatase inhibitor 1; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D002118:Calcium