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Center for Cell Signaling, Department of Microbiology, Health Sciences Center, University of Virginia, Charlottesville, VA 22908

Correspondence to Xinyu Chen: xc2d{at}virginia.edu

Abstract
The polarity protein Par-3 plays critical roles in axon specification and the establishment of epithelial apico-basal polarity. Par-3 associates with Par-6 and atypical protein kinase C and is required for the proper assembly of tight junctions, but the molecular basis for its functions is poorly understood. We now report that depletion of Par-3 elevates the phosphorylated pool of cofilin, a key regulator of actin dynamics. Expression of a nonphosphorylatable mutant of cofilin partially rescues tight junction assembly in cells lacking Par-3, as does the depletion of LIM kinase 2 (LIMK2), an upstream kinase for cofilin. Par-3 binds to LIMK2 but not to the related kinase LIMK1. Par-3 inhibits LIMK2 activity in vitro, and overexpressed Par-3 suppresses cofilin phosphorylation that is induced by lysophosphatidic acid. Our findings identify LIMK2 as a novel target of Par-3 and uncover a molecular mechanism by which Par-3 could regulate actin dynamics during cell polarization.

Abbreviations used in this paper: aPKC, atypical PKC; HCM, high calcium medium; KD, knockdown; LCM, low calcium medium; LIMK, LIM kinase; LPA, lysophosphatidic acid; NRG, neuregulin; RNAi, RNA interference; ROCK, Rho-associated kinase; shRNA, short hairpin RNA; TER, transepithelial electrical resistance.

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