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

• Published in: The Journal of cell biology Vol. 191; no. 2; pp. 367 - 381
• Main Authors: Yoshimura, Shin-ichiro, Gerondopoulos, Andreas, Linford, Andrea, Rigden, Daniel J, Barr, Francis A
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 18-10-2010; Rockefeller University Press
• Subjects: Antibodies; Binding sites; Biological Transport; Cell membranes; Cells; Endosomes; Epithelial cells; Guanine Nucleotide Exchange Factors - analysis; Guanine Nucleotide Exchange Factors - chemistry; Guanine Nucleotide Exchange Factors - physiology; HeLa Cells; Humans; Kidney cells; Lysosomes - metabolism; Membranes; Physiological regulation; Protein Structure, Tertiary; Proteins; rab GTP-Binding Proteins - analysis; rab GTP-Binding Proteins - chemistry; rab GTP-Binding Proteins - physiology; Recycling; Shiga Toxin - metabolism; T cell receptors; Toxins; Trans golgi network; trans-Golgi Network - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201008051

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.