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Vol. 18, Issue 10, 3788-3799, October 2007

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A Unique Element in the Cytoplasmic Tail of the Type II Transforming Growth Factor- Receptor Controls Basolateral Delivery

Stephen J. Murphy^*, Keren E. Shapira, Yoav I. Henis, and Edward B. Leof^*

*Thoracic Diseases Research Unit, Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905; and Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Submitted October 19, 2006; Revised July 9, 2007; Accepted July 11, 2007
Monitoring Editor: Keith Mostov

Transforming growth factor (TGF)- receptors stimulate diverse signaling processes that control a wide range of biological responses. In polarized epithelia, the TGF type II receptor (T2R) is localized at the basolateral membranes. Sequential cytoplasmic truncations resulted in receptor missorting to apical surfaces, and they indicated an essential targeting element(s) near the receptor's C terminus. Point mutations in the full-length receptor confirmed this prediction, and a unique basolateral-targeting region was elucidated between residues 529 and 538 (LTAxxVAxxR) that was distinct, but colocalized within a clinically significant signaling domain essential for TGF-dependent activation of the Smad2/3 cascade. Transfer of a terminal 84 amino-acid fragment, containing the LTAxxVAxxR element, to the apically sorted influenza hemagglutinin (HA) protein was dominant and directed basolateral HA expression. Although delivery to the basolateral surfaces was direct and independent of any detectable transient apical localization, fluorescence recovery after photobleaching demonstrated similar mobility for the wild-type receptor and a missorted mutant lacking the targeting motif. This latter finding excludes the possibility that the domain acts as a cell membrane retention signal, and it supports the hypothesis that T2R sorting occurs from an intracellular compartment.

Address correspondence to: Edward B. Leof (leof.edward{at}mayo.edu)