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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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Model for the integrin regulation of CKI-1.When ECM ligand binds to integrin on the cell surface, the IPP complex delivers signals to the SCF E3 ligase complex resulting in sequestration of CKI-1/p27 to the nucleolus. In pat-3(sp), the mutant β integrin interferes with the function of wild-type pat-3(+). Consequently, integrin does not signal to the IPP complex. We suggest the reduced integrin signals may leave the SCF complex inactive. This allows an increase in the amount of CKI-1/p27 and alters the location of the protein in the nucleus.
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pone-0042425-g006: Model for the integrin regulation of CKI-1.When ECM ligand binds to integrin on the cell surface, the IPP complex delivers signals to the SCF E3 ligase complex resulting in sequestration of CKI-1/p27 to the nucleolus. In pat-3(sp), the mutant β integrin interferes with the function of wild-type pat-3(+). Consequently, integrin does not signal to the IPP complex. We suggest the reduced integrin signals may leave the SCF complex inactive. This allows an increase in the amount of CKI-1/p27 and alters the location of the protein in the nucleus.

Mentions: We propose a potential model for the role of integrin signaling in CKI-1 regulation. Our preferred model assumes the presence of functional integrin in the hypodermal cells. Integrin is activated by binding to ECM ligands and signaling is initiated and propagated by molecules such as pat-4/ILK and unc-97/PINCH to SCF ligase which degrades CKI-1 (Figure 6). pat-3(sp) may interfere with the formation of the SCF complex and the degradation of CKI-1 by inhibiting the function of wild-type PAT-3 integrins or by acting as a non-functional β subunit that significantly dilutes integrin signaling [8]. SAGE analysis indicates that pat-3 and ina-1 are expressed in hypodermal cells [79], [80] consistent with a previously identified role for ina-1/α integrin function in hypodermis [24]. Although we have identified a role for the SCF complex in CKI-1 degradation, our work does not specifically address whether SCF activation is directly linked to integrin signaling in a linear manner, as displayed in the model (Figure 6). Future genetic studies should determine the cell autonomy and epistatic relationships of the genes in the pathway from integrin to cell cycle control.


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)

Model for the integrin regulation of CKI-1.When ECM ligand binds to integrin on the cell surface, the IPP complex delivers signals to the SCF E3 ligase complex resulting in sequestration of CKI-1/p27 to the nucleolus. In pat-3(sp), the mutant β integrin interferes with the function of wild-type pat-3(+). Consequently, integrin does not signal to the IPP complex. We suggest the reduced integrin signals may leave the SCF complex inactive. This allows an increase in the amount of CKI-1/p27 and alters the location of the protein in the nucleus.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042425-g006: Model for the integrin regulation of CKI-1.When ECM ligand binds to integrin on the cell surface, the IPP complex delivers signals to the SCF E3 ligase complex resulting in sequestration of CKI-1/p27 to the nucleolus. In pat-3(sp), the mutant β integrin interferes with the function of wild-type pat-3(+). Consequently, integrin does not signal to the IPP complex. We suggest the reduced integrin signals may leave the SCF complex inactive. This allows an increase in the amount of CKI-1/p27 and alters the location of the protein in the nucleus.
Mentions: We propose a potential model for the role of integrin signaling in CKI-1 regulation. Our preferred model assumes the presence of functional integrin in the hypodermal cells. Integrin is activated by binding to ECM ligands and signaling is initiated and propagated by molecules such as pat-4/ILK and unc-97/PINCH to SCF ligase which degrades CKI-1 (Figure 6). pat-3(sp) may interfere with the formation of the SCF complex and the degradation of CKI-1 by inhibiting the function of wild-type PAT-3 integrins or by acting as a non-functional β subunit that significantly dilutes integrin signaling [8]. SAGE analysis indicates that pat-3 and ina-1 are expressed in hypodermal cells [79], [80] consistent with a previously identified role for ina-1/α integrin function in hypodermis [24]. Although we have identified a role for the SCF complex in CKI-1 degradation, our work does not specifically address whether SCF activation is directly linked to integrin signaling in a linear manner, as displayed in the model (Figure 6). Future genetic studies should determine the cell autonomy and epistatic relationships of the genes in the pathway from integrin to cell cycle control.

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