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Vol. 17, Issue 2, 645-657, February 2006

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Extracellular Signal-regulated Kinase Regulates Clathrin-independent Endosomal Trafficking

Sarah E. Robertson ^*, Subba Rao Gangi Setty , Anand Sitaram ^*, Michael S. Marks , Robert E. Lewis , and Margaret M. Chou ^*

^* Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198

Submitted July 21, 2005; Revised October 26, 2005; Accepted November 14, 2005
Monitoring Editor: Sandra Schmid

Extracellular signal-regulated kinase (Erk) is widely recognized for its central role in cell proliferation and motility. Although 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, ADP-ribosylation factor 6 (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, within the expanded endosome. Treatment of cells with the mitogen-activated protein kinase kinase (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 kinase suppressor of Ras 1 accumulates at the Arf6 recycling compartment. The requirement for Erk was highly specific for this endocytic pathway, because 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.

Abbreviations used: Arf6, ADP-ribosylation factor 6; Erk, extracellular signal-regulated kinase; KSR, kinase suppressor of Ras; MHCI, class I major histocompatibility complex.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Margaret M. Chou (mmc{at}mail.med.upenn.edu).