The sorbin homology domain: A motif for the targeting of proteins to lipid rafts

doi:10.1073/pnas.151252898

The sorbin homology domain: A motif for the targeting of proteins to lipid rafts

Department of Internal Medicine and Physiology, Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109

Communicated by Pedro M. Cuatrecasas, University of California, San Diego School of Medicine, Rancho Santa Fe, CA (received for review March 21, 2001)

Abstract

On phosphorylation of Cbl, the c-Cbl-associated protein (CAP)/Cbl complex dissociates from the insulin receptor and translocates to a lipid raft membrane fraction to form a ternary complex with flotillin. Deletion analyses of the CAP gene identified a 115-aa region responsible for flotillin binding. This region is homologous to the peptide sorbin and is referred to as the sorbin homology (SoHo) domain. This domain is present in two other proteins, vinexin and ArgBP2. Vinexin also interacted with flotillin, and deletion of its SoHo domain similarly blocked flotillin binding. The overexpression of a CAP mutant in which the SoHo domain had been deleted (CAPΔSoHo) prevented the translocation of Cbl to lipid rafts and subsequently blocked the recruitment of CrkII and C3G. Moreover, overexpression of CAPΔSoHo prevented the stimulation of glucose transport and GLUT4 translocation by insulin. These results suggest a mechanism for localization of signaling proteins to the lipid raft that mediates the compartmentalization of crucial signal transduction pathways.

Footnotes

↵ * Present address: Discovery Biology, 3-Dimensional Pharmaceuticals, Exton, Philadelphia, PA 19341.
↵ † To whom reprint requests should be addressed at: Life Sciences Institute, Department of Internal Medicine and Physiology, MSRB I, Room 4520, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0650. E-mail: saltiel{at}umich.edu.
Abbreviations:

CAP,

c-Cbl-associated protein;

SoHo,

sorbin homology;

HEK,

human embryo kidney;

GST,

glutathione S-transferase;

EGFP,

enhanced green fluorescence protein;

IRAP,

insulin-responsive aminopeptidase;

CI/M6PR,

cation-independent mannose-6-phosphate receptor