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Authors: Nicole A. Ducharme, Amy-Joan L. Ham, Lynne A. Lapierre and James R. Goldenring

Nicole A. Ducharme

Departments of Surgery and Cell & Developmental Biology; Vanderbilt University School of Medicine; Nashville, TN USA

Amy-Joan L. Ham

Department of Biochemistry and the Mass Spectrometry Research Center; Vanderbilt University School of Medicine; Nashville, TN USA

Lynne A. Lapierre

Departments of Surgery and Cell & Developmental Biology; Vanderbilt University School of Medicine; Nashville, TN USA and Nashville VA Medical Center; Nashville, TN USA

James R. Goldenring

Corresponding author: jim.goldenring@vanderbilt.edu
Departments of Surgery and Cell & Developmental Biology; Vanderbilt University School of Medicine; Nashville, TN USA; Nashville VA Medical Center; Nashville, TN USA; Vanderbilt-Ingram Cancer Center; Nashville TN USA

Abstract:
The Rab11 Family Interacting Proteins (Rab11-FIPs) are hypothesized to regulate sequential steps in the apical recycling and transcytotic pathways of polarized epithelial cells. Previous studies have suggested that Rab11-FIP proteins assemble into multi-protein complexes regulating plasma membrane recycling. Rab11-FIP2 interacts with both myosin Vb and Rab11. Recent investigations have noted that that Rab11-FIP2 mutants [Rab11-FIP2(129–512), also designated Rab11-FIP2(ΔC2) and Rab11-FIP2(S229A, R413G), also designated Rab11-FIP2(SARG)], are potent inhibitors of transcytosis in polarized MDCK cells. Interestingly, Rab11-FIP2(ΔC2), but not Rab11-FIP2(SARG), also altered the morphology of the EEA-1 positive early endosomal compartment. These findings suggested that Rab11-FIP2 mutants could differentiate different points along the recycling pathway. We therefore sought to investigate whether Rab11-FIP2 is a general regulator of the early endosomal system. Both Rab11-FIP2 mutants altered the localization and co-localized with dynein heavy chain. In contrast, both clathrin heavy chain and AP-1 accumulated with membranes containing Rab11-FIP2(SARG), but not with Rab11-FIP2(ΔC2). Expression of Rab11-FIP2(ΔC2), but not Rab11-FIP2(SARG), caused clustering of early endosomal markers Rab5b, Epsin 4 and IQGAP1, around a collapsed Rab11-FIP2 containing membranous cisternum. Interestingly, neither Rab11-FIP2 mutant had any effect on the distribution of Rab5a, a classical early endosome marker. The results support the view that Rab11-FIP2 may influence microtubule-dependent centripetal movement of subsets of early endosomes as well as processing through the common and recycling endosomal systems.

Received: December 20, 2010; Accepted: February 25, 2011

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