Han Jianzhong, Han Liang, Tiwari Priyanka, Wen Zhexing, Zheng James Q
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
J Cell Biol. 2007 Jan 1;176(1):101-11. doi: 10.1083/jcb.200607128.
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.
第二信使环磷酸腺苷（cAMP）在轴突生长和导向中起关键作用，但其下游机制仍不清楚。在本研究中，我们报道II型蛋白激酶A（PKA）在生长锥丝状伪足中高度富集，这种空间定位使得cAMP信号能够与其特定效应器偶联，从而调节导向反应。破坏PKA在丝状伪足中的定位会损害cAMP介导的生长锥吸引，并阻止cAMP升高将排斥反应转变为吸引反应。我们的数据进一步表明，PKA通过磷酸化调节蛋白抑制剂-1（I-1）来靶向蛋白磷酸酶-1（PP1），以促进生长锥吸引。最后，我们发现I-1和PP1介导髓磷脂相关糖蛋白诱导的生长锥排斥。这些发现表明，II型PKA在生长锥丝状伪足中的空间定位在cAMP对生长锥运动性和导向的调节中起重要作用。
