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A more recent version of this article appeared on February 1, 2006
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Submitted on July 21, 2005
Revised on October 26, 2005
Accepted on November 14, 2005
Departments of *Cell and Developmental Biology and Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198
Monitoring Editor: Sandra Schmid
Extracellular signal-regulated kinase (Erk) is widely recognized for its central role in cell proliferation and motility. While previous work has shown that Erk is localized at endosomal compartments, no role for Erk in regulating endosomal trafficking has been demonstrated. Here we report that Erk signaling regulates trafficking through the clathrin-independent, Arf6 GTPase-regulated endosomal pathway. Inactivation of Erk induced by a variety of methods leads to a dramatic expansion of the Arf6 endosomal recycling compartment, and intracellular accumulation of cargo, such as class I major histocompatibility complex (MHCI), within the expanded endosome. Treatment of cells with the MEK inhibitor U0126 reduces surface expression of MHCI without affecting its rate of endocytosis, suggesting that inactivation of Erk perturbs recycling. Furthermore, under conditions where Erk activity is inhibited, a large cohort of Erk, MEK, and the Erk scaffold, KSR1, accumulates at the Arf6 recycling compartment. The requirement for Erk was highly specific for this endocytic pathway, as its inhibition had no effect on trafficking of cargo of the classical clathrin-dependent pathway. These studies reveal a previously unappreciated link of Erk signaling to organelle dynamics and endosomal trafficking.
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