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Impaired Crkl Expression Contributes to the Defective DNA Binding of Stat5b in Nonobese Diabetic Mice

¹ Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, Georgia
² Molecular Reproduction Unit, Rajiv Gandhi Centre for Biotechnology, Kerala, India
³ Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida
⁴ Diabetes Research Center and Departments of Microbiology and Internal Medicine, University of Virginia, Charlottesville, Virginia

Address correspondence and reprint requests to Dr. Jin-Xiong She, Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th St., PV6B108, Augusta, GA 30912. E-mail: jshe{at}mail.mcg.edu; or Dr. Malini Laloraya, Molecular Reproduction Unit, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram-695 014, Kerala, India. E-mail: laloraya{at}rgcb.res.in

Abbreviations: ECL, enhanced chemiluminescence; EMSA, electrophoretic mobility shift assay; GMCSF, granulocyte macrophage colony–stimulating factor; TCR, T-cell receptor

A point mutation in the Stat5b DNA binding domain in the nonobese diabetic (NOD) mouse was shown to have weaker DNA binding compared with the B6 Stat5b. Here, we assessed the binding ability of the mutant Stat5b in the B6 genetic background (B6.NOD-c11) and the wild-type Stat5b in the NOD background (NOD.Lc11). To our surprise, the binding ability of Stat5b is inconsistent with the presence or absence of the Stat5b mutation in these congenic mice but is correlated with the expression levels of the Crkl protein, which was coprecipitated by an anti-Stat5b antibody. Both the expression of Crkl and the Stat5b binding ability are the highest in B6.NOD-c11 and the lowest in NOD while intermediate in B6 and NOD.Lc11 mice. We demonstrated that the adapter molecule Crkl can bind Stat5b and that the Crkl protein is a Stat5b binding cofactor. More importantly, profection of Crkl recombinant protein significantly increased Stat5b binding ability and rescued the binding defect of the NOD mutant Stat5b, suggesting that Crkl is a key regulatory molecule for Stat5b binding. Therefore, the defective Crkl expression may contribute to the development of diabetes in the NOD mice by exacerbating the defective Stat5b binding ability.

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