title: Ral's engagement with the exocyst: breaking up is hard to do.
abstract: Small GTPases are key intermediates that operate at the crossroads of signaling and trafficking. During insulin-stimulated glucose transport, activation of the vesicular-localized small GTPase RalA leads to its engagement with the vesicle tethering exocyst complex, mediating the plasma membrane targeting of Glut4 vesicles. Activation of RalA is achieved via inhibition of the Ral GAP Complex (RGC), comprised of the regulatory subunit RGC1 and the catalytic subunit RGC2. RGC1/2 share homology with the Rheb GAP complex TSC1/2 and can also be inactivated by Akt-catalyzed phosphorylation to produce RalA activation and exocyst engagement. Disengagement between the GTPase and the exocyst occurs through phosphorylation of its effector Sec5 in its Ral-binding domain, thus allowing continuation of exocytic program and recycling of the tether. Phosphorylation of Sec5 is catalyzed by protein kinase C (PKC) and can be reversed by an exocyst-associated phosphatase activity. Therefore, integration of the GTPase cycle and the phosphorylation cycle orchestrates the engagement-disengagement switch between Ral GTPases and the effector exocyst.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D005089:Exocytosis; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C470182:EXOC2 protein, human; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; C514562:RALGAPA2 protein, human; C484658:RAP1GAP protein, human; C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D020725:ral GTP-Binding Proteins