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MBC in Press, published online ahead of print June 6, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0172

A more recent version of this article appeared on August 1, 2007
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Submitted on February 26, 2007
Revised on May 18, 2007
Accepted on May 24, 2007

Naked2 Acts as a Cargo Recognition and Targeting Protein to Ensure Proper Delivery and Fusion of TGF-{alpha}-containing Exocytic Vesicles at the Lower Lateral Membrane of Polarized MDCK Cells

Cunxi Li,* Mingming Hao,{dagger} Zheng Cao,* Wei Ding,* Ramona Graves-Deal,* Jianyong Hu,* David W. Piston,{dagger} and Robert J. Coffey*{sect}

Departments of *Medicine and Cell and Developmental Biology and {dagger}Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232; {sect}Department of Veterans Affairs Medical Center, Nashville, TN 37232-2279

Monitoring Editor: Jennifer Lippincott-Schwartz

TGF-{alpha} is the major autocrine EGF receptor ligand in vivo. In polarized epithelial cells, proTGF-{alpha} is synthesized and then delivered to the basolateral cell surface. We previously reported that Naked2 interacts with basolateral sorting determinants in the cytoplasmic tail of a Golgi-processed form of TGF-{alpha} and that TGF-{alpha} is not detected at the basolateral surface of MDCK cells expressing myristoylation-deficient (G2A) Naked2. By high resolution microscopy, we now show that wild type, but not G2A, Naked2-associated vesicles fuse at the plasma membrane. We further demonstrate that Naked2-associated vesicles are delivered to the lower lateral membrane of polarized MDCK cells independent of µ1B adaptin. We identify a basolateral targeting segment within Naked2; residues 1-173 redirect NHERF-1 from the apical cytoplasm to the basolateral membrane and internal deletion of residues 37-104 results in apical mislocalization of Naked2 and TGF-{alpha}. shRNA knockdown of Naked2 leads to a dramatic reduction in the 16-kDa cell surface isoform of TGF-{alpha} and increased cytosolic TGF-{alpha} immunoreactivity. We propose that Naked2 acts as a cargo recognition and targeting (CaRT) protein to ensure proper delivery, tethering and fusion of TGF-{alpha}-containing vesicles to a distinct region at the basolateral surface of polarized epithelial cells.

Address correspondence to: Robert J. Coffey (robert.coffey{at}vanderbilt.edu)




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