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J. Biol. Chem., Vol. 281, Issue 11, 7302-7308, March 17, 2006

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Membrane-associated STAT3 and PY-STAT3 in the Cytoplasm^*

Mehul Shah, Kirit Patel, Somshuvra Mukhopadhyay, Fang Xu, Gary Guo, and Pravin B. Sehgal¹

From the Departments of Cell Biology and Anatomy and Medicine, New York Medical College, Valhalla, New York 10595

Signal transduction from the plasma membrane to the nucleus by STAT proteins is widely represented as exclusively a soluble cytosolic process. Using cell-fractionation methods, we observed that 5% of cytoplasmic STAT3 was constitutively associated with the purified early endosome (EE) fraction in human Hep3B liver cells. By 15-30 min after interleukin-6 (IL-6) treatment, up to two-thirds of cytoplasmic Tyr-phosphorylated STAT3 can be associated with the purified early endosome fraction (Rab-5-, EEA1-, transferrin receptor-, and clathrin-positive fraction). Electron microscopy, immunofluorescence, and detergent dissection approaches confirmed the association of STAT3 and PY-STAT3 with early endosomes. STAT3 was constitutively associated with clathrin heavy chain in membrane and in the 1- to 2-MDa cytosolic complexes. The membrane association was dynamic in that, within 15 min of treatment with the vicinal-thiol cross-linker phenylarsine oxide, there was a dramatic increase in bulk STAT3 association with sedimentable membranes. The functional contribution of PY-STAT3 association with the endocytic pathway was evaluated in transient transfection assays using IL-6-inducible STAT3-reporter-luciferase constructs and selective regulators of this pathway. STAT3-transcriptional activation was inhibited by expression constructs for dominant negative dynamin K44A, epsin 2a, amphiphysin A1, and clathrin light chain but enhanced by that for the active dynamin species MxA. Taken together, these studies emphasize the contribution of the endocytic pathway to productive IL-6/STAT3 signaling.

Received for publication, August 3, 2005 , and in revised form, December 27, 2005.

^* This work was supported, in part, by Research Grant HL-73301 from the National Institutes of Health and by a Dissertation Research Award (to M. S.) from the Susan G. Komen Breast Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Cell Biology & Anatomy, New York Medical College, Rm. 201, Basic Sciences Bldg., Valhalla, NY 10595. Tel.: 914-594-4196; Fax: 914-594-4825; E-mail: pravin_sehgal{at}nymc.edu.

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