No abstract

Rho family GTPases, particularly Rac1 and Cdc42, are key regulators of cell polarization and directional migration. Adenomatous polyposis coli (APC) is also thought to play a pivotal role in polarized cell migration. We have found that IQGAP1, an effector of Rac1 and Cdc42, interacts directly with APC. IQGAP1 and APC localize interdependently to the leading edge in migrating Vero cells, and activated Rac1/Cdc42 form a ternary complex with IQGAP1 and APC. Depletion of either IQGAP1 or APC inhibits actin meshwork formation and polarized migration. Depletion of IQGAP1 or APC also disrupts localization of CLIP-170, a microtubule-stabilizing protein that interacts with IQGAP1. Taken together, these results suggest a model in which activation of Rac1 and Cdc42 in response to migration signals leads to recruitment of IQGAP1 and APC which, together with CLIP-170, form a complex that links the actin cytoskeleton and microtubule dynamics during cell polarization and directional migration.

The dynamic rearrangement of cell-cell adhesion is one of the major physiological events in tissue development and tumor metastasis. Polarized cell migration, another key event, is a tightly regulated process that occurs during tissue development, chemotaxis and wound healing. Rho-family small GTPases, especially Rac1 and Cdc42, play pivotal roles in these processes through one of their effectors, IQGAP1. Recent studies reveal that IQGAP1 regulates cadherin-mediated cell-cell adhesion both positively and negatively. It captures and stabilizes microtubules through the microtubule-binding protein CLIP-170 near the cell cortex, leading to establishment of polarized cell morphology and directional cell migration. Furthermore, Rac1 and Cdc42 link the adenomatous polyposis coli (APC) protein to actin filaments through IQGAP1 at the leading edge and thereby regulate polarization and directional migration.

cIn China, a majority of the highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRSV) strains were seeded by the 2006 outbreak. However, the most recently emerged (2013-2014) HP-PRRSV strain has a very different genetic background. It is a NADC30-like PRRSV strain recently introduced from North America that has undergone genetic exchange with the classic HP-PRRSV strains in China. Subsequent isolation and characterization of this variant suggest high pathogenicity, so it merits special attention in control and vaccine strategies. P orcine reproductive and respiratory syndrome (PRRS) is characterized by respiratory distress in nursery swine and reproductive failure in sows and has resulted in huge economic losses to the global swine industry since its first recognition in the United States in 1987 (1). In China, highly pathogenic PRRSV (HP-PRRSV) has been circulating and predominating in the field since the initial outbreak in 2006 and has resulted in the loss of more than one million pigs (2-5). Retrospective studies of that outbreak have shown that the highly pathogenic variant emerged from less pathogenic PRRSV strains in China (6), which were initially introduced from North America in the 1990s. CH-1a was the earliest representative of this group (7). Following the outbreak, more-stringent biosecurity controls and a targeted immunization campaign were undertaken to limit HP-PRRS in China.However, despite these measures, HP-PRRSV has experienced recurrent population expansions since the initial outbreak. One such reemergence was associated with genetic exchange between two HP-PRRSV viruses circulating in the field (8). Another recent outbreak (2013)(2014) is probably in the early stage of emergence. It has occurred in several provinces of China and is characterized by high fever, cough, anorexia, red discoloration of the body, and blue ears. Diseased pigs also have multiple visceral lesions. Their lungs display consolidation, and their lymph nodes are enlarged and hemorrhagic. The rates of morbidity and mortality due to this new HP-PRRSV are very high. An affected farm in Jilin Province had a morbidity rate of 100% and a mortality rate of 76.6% (230/ 300).We obtained the representative open reading frame 5 (ORF5) sequences from two farms that experienced the disease, i.e., JL580 and HLJ58 from Jilin Province and Heilongjiang Province, respectively. Phylogenetic analyses using the PhyML version 3.0 software (9) suggested that these viruses are distantly related to the classic HP-PRRSV strains in China, which belong to lineage 8 (Fig. 1A). Instead, they nested deeply within diverse lineage 1, which originated in Canada and is now prevalent in both the United States and Canada (10). Interestingly, the virus is also closely related to a group represented by NADC30, a moderately virulent strain isolated in 2008 in the United States (11). Furthermore, the phylogenetic topology of the diversity surrounding this new HP-PRRSV suggests, with high resolution, a transmission chain from Canada to the Unit...