Par-3 mediates the inhibition of LIM kinase 2 to regulate cofilin phosphorylation and tight junction assembly.
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.
Chen
Xinyu
X
Center for Cell Signaling, Department of Microbiology, Health Sciences Center, University of Virginia, Charlottesville, VA 22908, USA. xc2d@virginia.edu
Macara
Ian G
IG
D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D019108:Tight Junctions / Q000378:metabolism* / Q000502:physiology
D051339:Actin Depolymerizing Factors; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C102895:LIMK2 protein, human; D054461:Lim Kinases; C097238:PAR-3 protein, C elegans; D017346:Protein Serine-Threonine Kinases