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Jak3-Independent Trafficking of the Common Chain Receptor Subunit: Chaperone Function of Jaks Revisited

Sigrun R. Hofmann,^1*, Albert Q. Lam,^1,2, Stephan Frank,^1,3 Yong-Jie Zhou,¹ Haydeé L. Ramos,¹ Yuka Kanno,¹ Davide Agnello,¹ Richard J. Youle,⁴ and John J. O'Shea¹

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases,¹ Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health,⁴ Howard Hughes Medical Institute-National Institutes of Health Research Scholar's Program, Bethesda, Maryland,² Department of Neuropathology, Bonn University Medical Center, Bonn, Germany³

Received 29 October 2003/ Returned for modification 14 December 2003/ Accepted 11 February 2004

Janus kinases (Jaks) play an essential role in cytokine signaling and have been reported to regulate plasma membrane expression of their cognate receptors. In this study, we examined whether Jak3 and the common chain (_c) reciprocally regulate their plasma membrane expression. In contrast to interleukin-2R, _c localized poorly to the plasma membrane and accumulated in endosomal-lysosomal compartments. However, _c was expressed at comparable levels on the surface of cells lacking Jak3, and plasma membrane turnover of _c was independent of Jak3. Nonetheless, overexpression of Jak3 enhanced accumulation of _c at the plasma membrane. Without _c, Jak3 localized in the cytosol, whereas in the presence of the receptor, it colocalized with _c in endosomes and at the plasma membrane. Although the Jak FERM domain is necessary and sufficient for receptor binding, the requirement for full-length Jak3 in _c membrane trafficking was remarkably stringent; using truncation and deletion mutants, we showed that the entire Jak3 molecule was required, although kinase activity was not. Thus, unlike other cytokine receptors, _c does not require Jak3 for receptor membrane expression. However, full-length Jak3 is required for normal trafficking of this cytokine receptor/Jak pair, a finding that has important structural and clinical implications.

S.R.H. and A.Q.L. contributed equally to this study.

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