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J Cell Biol. 2010 Oct 18;191(2):367-81. doi: 10.1083/jcb.201008051. Epub 2010 Oct 11.

Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors.

Author information

  • 1Cancer Research Centre and 2 Institute of Integrative Biology, University of Liverpool, Liverpool L3 9TA, England, UK.

Abstract

A key requirement for Rab function in membrane trafficking is site-specific activation by GDP-GTP exchange factors (GEFs), but the majority of the 63 human Rabs have no known GEF. We have performed a systematic characterization of the 17 human DENN domain proteins and demonstrated that they are specific GEFs for 10 Rabs. DENND1A/1B localize to clathrin patches at the plasma membrane and activate Rab35 in an endocytic pathway trafficking Shiga toxin to the trans-Golgi network. DENND2 GEFs target to actin filaments and control Rab9-dependent trafficking of mannose-6-phosphate receptor to lysosomes. DENND4 GEFs target to a tubular membrane compartment adjacent to the Golgi, where they activate Rab10, which suggests a function in basolateral polarized sorting in epithelial cells that compliments the non-DENN GEF Sec2 acting on Rab8 in apical sorting. DENND1C, DENND3, DENND5A/5B, MTMR5/13, and MADD activate Rab13, Rab12, Rab39, Rab28, and Rab27A/27B, respectively. Together, these findings provide a basis for future studies on Rab regulation and function.

PMID:
20937701
[PubMed - indexed for MEDLINE]
PMCID:
PMC2958468
Free PMC Article

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