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Molecular and Cellular Biology, October 2004, p. 9092-9101, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.9092-9101.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome

Bao Q. Vuong,1 Teresita L. Arenzana,1 Brian M. Showalter,2 Julie Losman,2 X. Peter Chen,2 Justin Mostecki,1 Alexander S. Banks,1 Andre Limnander,3 Neil Fernandez,2 and Paul B. Rothman1,2,3*

Departments of Microbiology,1 Medicine,2 Integrated Program in Molecular, Cellular, and Biophysical Studies, College of Physicians and Surgeons, Columbia University, New York, New York3

Received 31 December 2003/ Returned for modification 13 February 2004/ Accepted 15 June 2004

The regulation of cytokine signaling is critical for controlling cellular proliferation and activation during an immune response. SOCS-1 is a potent inhibitor of Jak kinase activity and of signaling initiated by several cytokines. SOCS-1 protein levels are tightly regulated, and recent data suggest that SOCS-1 may regulate the protein levels of some signaling proteins by the ubiquitin proteasome pathway; however, the cellular mechanism by which SOCS-1 directs proteins for degradation is unknown. In this report, SOCS-1 is found to colocalize and biochemically copurify with the microtubule organizing complex (MTOC) and its associated 20S proteasome. The SOCS-1 SH2 domain is required for the localization of SOCS-1 to the MTOC. Overexpression of SOCS-1 targets Jak1 in an SH2-dependent manner to a perinuclear distribution resembling the MTOC-associated 20S proteasome. Analysis of MTOCs fractionated from SOCS-1-deficient cells demonstrates that SOCS-1 may function redundantly to regulate the localization of Jak1 to the MTOC. Nocodazole inhibits the protein turnover of SOCS-1, demonstrating that the minus-end transport of SOCS-1 to the MTOC-associated 20S proteasome is required to regulate SOCS-1 protein levels. These data link SOCS-1 directly with the proteasome pathway and suggest another function for the SH2 domain of SOCS-1 in the regulation of Jak/STAT signaling.

* Corresponding author. Mailing address: 8-425 P&S Bldg., Columbia University, New York, NY 10032. Phone: (212) 305-1984. Fax: (212) 305-1870. E-mail: pbr3{at}columbia.edu.

Molecular and Cellular Biology, October 2004, p. 9092-9101, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.9092-9101.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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