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A novel mutation in β integrin reveals an integrin-mediated interaction between the extracellular matrix and cki-1/p27KIP1.

Kihira S, Yu EJ, Cunningham J, Cram EJ, Lee M - PLoS ONE (2012)

Bottom Line: RNAi of unc-52/perlecan, ina-1/α integrin, pat-4/ILK, and unc-97/PINCH resulted in abnormal CKI-1::GFP localization.These data also suggest that integrin plays a major role in maintaining proper CKI-1/p27(KIP1) levels in the cell.Perturbed integrin signaling may lead to the inhibition of SCF ligase activity, mislocalization and elevation of CKI-1/p27(KIP1).

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Baylor University, Waco, Texas, United States of America.

ABSTRACT
The cell-extracellular matrix (ECM) interaction plays an essential role in maintaining tissue shapes and regulates cell behaviors such as cell adhesion, differentiation and proliferation. The mechanism by which the ECM influences the cell cycle in vivo is poorly understood. Here we demonstrate that the β integrin PAT-3 regulates the localization and expression of CKI-1, a C. elegans homologue of the cyclin dependent kinase inhibitor p27(KIP1). In nematodes expressing wild type PAT-3, CKI-1::GFP localizes primarily to nucleoli in hypodermal cells, whereas in animals expressing mutant pat-3 with a defective splice junction, CKI-1::GFP appears clumped and disorganized in nucleoplasm. RNAi analysis links cell adhesion genes to the regulation of CKI-1. RNAi of unc-52/perlecan, ina-1/α integrin, pat-4/ILK, and unc-97/PINCH resulted in abnormal CKI-1::GFP localization. Additional RNAi experiments revealed that the SCF E3 ubiquitin-ligase complex genes, skpt-1/SKP2, cul-1/CUL1 and lin-23/F-box, are required for the proper localization and expression of CKI-1, suggesting that integrin signaling and SCF E3 ligase work together to regulate the cellular distribution of CKI-1. These data also suggest that integrin plays a major role in maintaining proper CKI-1/p27(KIP1) levels in the cell. Perturbed integrin signaling may lead to the inhibition of SCF ligase activity, mislocalization and elevation of CKI-1/p27(KIP1). These results suggest that adhesion signaling is crucial for cell cycle regulation in vivo.

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Sequences of the PAT-3 cytoplasmic tails.Wild type and mutant PAT-3 tails are compared to human β1A, β1B, and β1C cytoplasmic tails. Location of intron 7 is indicated by the red arrow.
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pone-0042425-g001: Sequences of the PAT-3 cytoplasmic tails.Wild type and mutant PAT-3 tails are compared to human β1A, β1B, and β1C cytoplasmic tails. Location of intron 7 is indicated by the red arrow.

Mentions: PAT-3 β integrin is expressed in virtually all tissues in the nematode C. elegans[37], and is required for muscle development and function. Null mutations in pat-3 cause a fully penetrant embryonic arrest due to defective muscle elongation [25], [38]. Previously, we created a mutation at the intron 7 splice junction in the cytoplasmic tail of PAT-3 integrin (Figure 1) [3], [34]. The transgenic rescued line, pat-3(sp), is viable but exhibits cold-sensitive larval arrest with gonad and muscle defects. We found that pat-3(sp) expresses the non-spliced as well as the spliced pat-3 mRNA, suggesting that mutant pat-3 might inhibit the function of wild type pat-3. In this study, we have expanded our analysis to investigate the molecular function of pat-3(sp)[34].


A novel mutation in β integrin reveals an integrin-mediated interaction between the extracellular matrix and cki-1/p27KIP1.

Kihira S, Yu EJ, Cunningham J, Cram EJ, Lee M - PLoS ONE (2012)

Sequences of the PAT-3 cytoplasmic tails.Wild type and mutant PAT-3 tails are compared to human β1A, β1B, and β1C cytoplasmic tails. Location of intron 7 is indicated by the red arrow.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412830&req=5

pone-0042425-g001: Sequences of the PAT-3 cytoplasmic tails.Wild type and mutant PAT-3 tails are compared to human β1A, β1B, and β1C cytoplasmic tails. Location of intron 7 is indicated by the red arrow.
Mentions: PAT-3 β integrin is expressed in virtually all tissues in the nematode C. elegans[37], and is required for muscle development and function. Null mutations in pat-3 cause a fully penetrant embryonic arrest due to defective muscle elongation [25], [38]. Previously, we created a mutation at the intron 7 splice junction in the cytoplasmic tail of PAT-3 integrin (Figure 1) [3], [34]. The transgenic rescued line, pat-3(sp), is viable but exhibits cold-sensitive larval arrest with gonad and muscle defects. We found that pat-3(sp) expresses the non-spliced as well as the spliced pat-3 mRNA, suggesting that mutant pat-3 might inhibit the function of wild type pat-3. In this study, we have expanded our analysis to investigate the molecular function of pat-3(sp)[34].

Bottom Line: RNAi of unc-52/perlecan, ina-1/α integrin, pat-4/ILK, and unc-97/PINCH resulted in abnormal CKI-1::GFP localization.These data also suggest that integrin plays a major role in maintaining proper CKI-1/p27(KIP1) levels in the cell.Perturbed integrin signaling may lead to the inhibition of SCF ligase activity, mislocalization and elevation of CKI-1/p27(KIP1).

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Baylor University, Waco, Texas, United States of America.

ABSTRACT
The cell-extracellular matrix (ECM) interaction plays an essential role in maintaining tissue shapes and regulates cell behaviors such as cell adhesion, differentiation and proliferation. The mechanism by which the ECM influences the cell cycle in vivo is poorly understood. Here we demonstrate that the β integrin PAT-3 regulates the localization and expression of CKI-1, a C. elegans homologue of the cyclin dependent kinase inhibitor p27(KIP1). In nematodes expressing wild type PAT-3, CKI-1::GFP localizes primarily to nucleoli in hypodermal cells, whereas in animals expressing mutant pat-3 with a defective splice junction, CKI-1::GFP appears clumped and disorganized in nucleoplasm. RNAi analysis links cell adhesion genes to the regulation of CKI-1. RNAi of unc-52/perlecan, ina-1/α integrin, pat-4/ILK, and unc-97/PINCH resulted in abnormal CKI-1::GFP localization. Additional RNAi experiments revealed that the SCF E3 ubiquitin-ligase complex genes, skpt-1/SKP2, cul-1/CUL1 and lin-23/F-box, are required for the proper localization and expression of CKI-1, suggesting that integrin signaling and SCF E3 ligase work together to regulate the cellular distribution of CKI-1. These data also suggest that integrin plays a major role in maintaining proper CKI-1/p27(KIP1) levels in the cell. Perturbed integrin signaling may lead to the inhibition of SCF ligase activity, mislocalization and elevation of CKI-1/p27(KIP1). These results suggest that adhesion signaling is crucial for cell cycle regulation in vivo.

Show MeSH
Related in: MedlinePlus