Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity

Abstract

Neurons polarize to form elaborate multiple dendrites and one long axon. The establishment and maintenance of axon/dendrite polarity are fundamentally important for neurons. Recent studies have demonstrated that the polarity complex PAR-3-PAR-6-atypical protein kinase C (aPKC) is involved in polarity determination in many tissues and cells. The function of the PAR-3-PAR-6-aPKC protein complex depends on its subcellular localization in polarized cells. PAR-3 accumulates at the tip of growing axons in cultured rat hippocampal neurons, but the molecular mechanism of this localization remains unknown. Here we identify a direct interaction between PAR-3 and KIF3A, a plus-end-directed microtubule motor protein, and show that aPKC can associate with KIF3A through its interaction with PAR-3. The expression of dominant-negative PAR-3 and KIF3A fragments that disrupt PAR-3-KIF3A binding inhibited the accumulation of PAR-3 and aPKC at the tip of the neurites and abolished neuronal polarity. These results suggest that PAR-3 is transported to the distal tip of the axon by KIF3A and that the proper localization of PAR-3 is required to establish neuronal polarity.

Phosphorylation of the Par Polarity Complex Protein Par3 at Serine 962 Is Mediated by Aurora A and Regulates Its Function in Neuronal Polarity

“…The Aurora A phosphorylation site is located close to the Par3-aPKCBC. This region of Par3 contains the binding sites for aPKC, Kif3A, Tiam-1, Stef, Mark2, and Numb (17,18,33,(37)(38)(39)(40)(41). However, preliminary results show that Aurora A phosphorylation does not affect the binding of these proteins.…”

“…Par3 and Par6 are present in all neurites of unpolarized neurons but become restricted to the axon in polarized stage 3 neurons, whereas active aPKC is found only at the tip of the axon (11,13,15). Par3 overexpression or suppression and aPKC inhibition result in defects in neuronal polarity and the loss of axons (14,15,(17)(18)(19). Par3 performs multiple function in neurons and mediates the transport of the Par complex and Smurf2 and the activation of Rac through Stef.…”

Cell polarity protein Par3 complexes with DNA-PK via Ku70 and regulates DNA double-strand break repair

“…served regulator of cell polarity that plays a central role in forming and maintaining TJs in vertebrate epithelial cells and in specifying neuronal polarity and also in determining asymmetric cell division [4][5][6][7][8]. The Drosophila orthologue of Par3, Bazooka, mediates the asymmetric localization of inscuteable in neuroblast asymmetric cell division and colocalizes with DaPKC and DmPar6 in the apical cortex [9].…”

Initiating and Growing an Axon

“…Neuroepithelial radial glia target the PAR3/6 complex in their apical domain along the ventricular wall (Manabe et al 2002;Costa et al 2008). Proteins reported to exist in a complex with PAR3/ 6 include atypical forms of protein kinase C (aPKC: PKCl and z) (Joberty et al 2000;Lin et al 2000;Qiu et al 2000), the small GTPase cdc42 (Joberty et al 2000;Lin et al 2000;Qiu et al 2000), the kinesin motor protein KIF3A (Nishimura et al 2004), the guanine exchange factor Tiam1/STEF (Chen and Macara 2005;Nishimura et al 2005), the lipid and protein phosphatase PTEN (von Stein et al 2005;Feng et al 2008), the GTPase activating protein (GAP) p190RhoGAP (Zhang and Macara 2008), the tumor suppressor lethal giant larvae (lgl) (Plant etal. 2003), the scaffold protein inscuteable (Schoberet al 1999), the ubiquitin ligases Smurf1 (Ozdamar et al 2005) and Smurf2 (Schwamborn et al 2007b), and the transforming growth factor receptor1 (TGFbR1) (Ozdamaret al 2005).…”