scholarly journals The IQGAP1-Rac1 and IQGAP1-Cdc42 Interactions

2007 ◽  
Vol 283 (3) ◽  
pp. 1692-1704 ◽  
Author(s):  
Darerca Owen ◽  
Louise J. Campbell ◽  
Keily Littlefield ◽  
Katrina A. Evetts ◽  
Zhigang Li ◽  
...  
Keyword(s):  
G Proteins ◽  
Binding Sites ◽  
Effector Proteins ◽  
Total Binding Energy ◽  
Relative Importance ◽  
Gtpase Activating Proteins ◽  
Cold Spots ◽  
Rho Family ◽  
Binding Interfaces ◽  
Small G Proteins

IQGAP1 contains a domain related to the catalytic portion of the GTPase-activating proteins (GAPs) for the Ras small G proteins, yet it has no RasGAP activity and binds to the Rho family small G proteins Cdc42 and Rac1. It is thought that IQGAP1 is an effector of Rac1 and Cdc42, regulating cell-cell adhesion through the E-cadherin-catenin complex, which controls formation and maintenance of adherens junctions. This study investigates the binding interfaces of the Rac1-IQGAP1 and Cdc42-IQGAP1 complexes. We mutated Rac1 and Cdc42 and measured the effects of mutations on their affinity for IQGAP1. We have identified similarities and differences in the relative importance of residues used by Rac1 and Cdc42 to bind IQGAP1. Furthermore, the residues involved in the complexes formed with IQGAP1 differ from those formed with other effector proteins and GAPs. Relatively few mutations in switch I of Cdc42 or Rac1 affect IQGAP1 binding; only mutations in residues 32 and 36 significantly decrease affinity for IQGAP1. Switch II mutations also affect binding to IQGAP1 although the effects differ between Rac1 and Cdc42; mutation of either Asp-63, Arg-68, or Leu-70 abrogate Rac1 binding, whereas no switch II mutations affect Cdc42 binding to IQGAP1. The Rho family “insert loop” does not contribute to the binding affinity of Rac1/Cdc42 for IQGAP1. We also present thermodynamic data pertaining to the Rac1/Cdc42-RhoGAP complexes. Switch II contributes a large portion of the total binding energy to these complexes, whereas switch I mutations also affect binding. In addition we identify “cold spots” in the Rac1/Cdc42-RhoGAP/IQGAP1 interfaces. Competition data reveal that the binding sites for IQGAP1 and RhoGAP on the small G proteins overlap only partially. Overall, the data presented here suggest that, despite their 71% identity, Cdc42 and Rac1 appear to have only partially overlapping binding sites on IQGAP1, and each uses different determinants to achieve high affinity binding.

scholarly journals Regulated CD44 Cleavage under the Control of Protein Kinase C, Calcium Influx, and the Rho Family of Small G Proteins

1999 ◽  
Vol 274 (36) ◽  
pp. 25525-25534 ◽  
Author(s):  
Isamu Okamoto ◽  
Yoshiaki Kawano ◽  
Mitsuhiro Matsumoto ◽  
Moritaka Suga ◽  
Kozo Kaibuchi ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
G Proteins ◽  
Calcium Influx ◽  
Kinase C ◽  
Rho Family ◽  
Small G Proteins

scholarly journals Roco Proteins and the Parkinson’s Disease-Associated LRRK2

2018 ◽  
Vol 19 (12) ◽  
pp. 4074 ◽  
Author(s):  
Jingling Liao ◽  
Quyen Hoang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
G Proteins ◽  
Conformational Changes ◽  
Effector Proteins ◽  
Cellular Processes ◽  
Current State ◽  
Specific Effector ◽  
Unique Domain ◽  
Small G Proteins

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.

scholarly journals Small G proteins as key regulators of pancreatic digestive enzyme secretion

2009 ◽  
Vol 296 (3) ◽  
pp. E405-E414 ◽  
Author(s):  
John A. Williams ◽  
Xuequn Chen ◽  
Maria E. Sabbatini
Keyword(s):  
G Proteins ◽  
Secretory Granule ◽  
Secretory Pathway ◽  
Digestive Enzyme ◽  
Pancreatic Acinar Cells ◽  
Cellular Processes ◽  
Granule Membrane ◽  
Target Membrane ◽  
Rho Family ◽  
Small G Proteins

Small GTP-binding (G) proteins act as molecular switches to regulate a number of cellular processes, including vesicular transport. Emerging evidence indicates that small G proteins regulate a number of steps in the secretion of pancreatic acinar cells. Diverse small G proteins have been localized at discrete compartments along the secretory pathway and particularly on the secretory granule. Rab3D, Rab27B, and Rap1 are present on the granule membrane and play a role in the steps leading up to exocytosis. Whether the function of these G proteins is simply to ensure appropriate targeting or if they are involved as regulatory molecules is discussed. Most evidence suggests that Rab3D and Rab27B play a role in tethering the secretory granule to its target membrane. Other Rabs have been identified on the secretory granule that are associated with different steps in the secretory pathway. The Rho family small G proteins RhoA and Rac1 also regulate secretion through remodeling of the actin cytoskeleton. Possible mechanisms for regulation of these G proteins and their effector molecules are considered.

scholarly journals Inhibition of small G proteins of the Rho family by statins or Clostridium difficile toxin B enhances cytokine-mediated induction of NO synthase II

2000 ◽  
Vol 131 (3) ◽  
pp. 553-561 ◽  
Author(s):  
Michael Hausding ◽  
Andrea Witteck ◽  
Fernando Rodriguez-Pascual ◽  
Christian Von Eichel-Streiber ◽  
Ulrich Förstermann ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
G Proteins ◽  
No Synthase ◽  
Toxin B ◽  
Clostridium Difficile Toxin ◽  
Rho Family ◽  
Clostridium Difficile Toxin B ◽  
Small G Proteins

scholarly journals Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members.

1996 ◽  
Vol 16 (7) ◽  
pp. 3707-3713 ◽  
Author(s):  
J A Frost ◽  
S Xu ◽  
M R Hutchison ◽  
S Marcus ◽  
M H Cobb
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
G Proteins ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Erk Pathway ◽  
Mitogen Activated Protein ◽  
Rho Family ◽  
Small G Proteins

The mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that are regulated by distinct extracellular stimuli. The currently known members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overexpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize with an activated form of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the ERK pathway.

scholarly journals Translocation of Src kinase to the cell periphery is mediated by the actin cytoskeleton under the control of the Rho family of small G proteins.

1996 ◽  
Vol 135 (6) ◽  
pp. 1551-1564 ◽  
Author(s):  
V J Fincham ◽  
M Unlu ◽  
V G Brunton ◽  
J D Pitts ◽  
J A Wyke ◽  
...  
Keyword(s):  
G Proteins ◽  
Focal Adhesions ◽  
Cytochalasin D ◽  
Mitogen Activated Protein Kinase ◽  
Stress Fibers ◽  
Cell Periphery ◽  
Double Labeling ◽  
Rho Family ◽  
Swiss 3T3 ◽  
Small G Proteins

We have isolated Swiss 3T3 subclones that are resistant to the mitogenic and morphological transforming effects of v-Src as a consequence of aberrant translocation of the oncoprotein under low serum conditions. In chicken embryo and NIH 3T3 fibroblasts under similar conditions, v-Src rapidly translocates from the perinuclear region to the focal adhesions upon activation of the tyrosine kinase, resulting in downstream activation of activator protein-1 and mitogen-activated protein kinase, which are required for the mitogenic and transforming activity of the oncoprotein. Since serum deprivation induces cytoskeletal disorganization in Swiss 3T3, we examined whether regulators of the cytoskeleton play a role in the translocation of v-Src, and also c-Src, in response to biological stimuli. Actin stress fibers and translocation of active v-Src to focal adhesions in quiescent Swiss 3T3 cells were restored by microinjection of activated Rho A and by serum. Double labeling with anti-Src and phalloidin demonstrated that v-Src localized along the reformed actin filaments in a pattern that would be consistent with trafficking in complexes along the stress fibers to focal adhesions. Furthermore, treatment with the actin-disrupting drug cytochalasin D, but not the microtubule-disrupting drug nocodazole, prevented v-Src translocation. In addition to v-Src, we observed that PDGF-induced, Rac-mediated membrane ruffling was accompanied by translocation of c-Src from the cytoplasm to the plasma membrane, an effect that was also blocked by cytochalasin D. Thus, we conclude that translocation of Src from its site of synthesis to its site of action at the cell membrane requires an intact cytoskeletal network and that the small G proteins of the Rho family may specify the peripheral localization in focal adhesions or along the membrane, mediated by their effects on the cytoskeleton.

scholarly journals Gain-of-function screen of α-transducin identifies an essential phenylalanine residue necessary for full effector activation

2018 ◽  
Vol 293 (46) ◽  
pp. 17941-17952 ◽  
Author(s):  
Shawn K. Milano ◽  
Chenyue Wang ◽  
Jon W. Erickson ◽  
Richard A. Cerione ◽  
Sekar Ramachandran
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Binding Sites ◽  
Effector Proteins ◽  
Α Subunit ◽  
Gtp Binding ◽  
Effector Activity ◽  
Α Subunits ◽  
Phenylalanine Residue ◽  
Stimulation Of

Two regions on the α subunits of heterotrimeric GTP-binding proteins (G-proteins), the Switch II/α2 helix (which changes conformation upon GDP–GTP exchange) and the α3 helix, have been shown to contain the binding sites for their effector proteins. However, how the binding of Gα subunits to their effector proteins is translated into the stimulation of effector activity is still poorly understood. Here, we took advantage of a reconstituted rhodopsin-coupled phototransduction system to address this question and identified a distinct surface and an essential residue on the α subunit of the G-protein transducin (αT) that is necessary to fully activate its effector enzyme, the cGMP phosphodiesterase (PDE). We started with a chimeric G-protein α subunit (αT*) comprising residues mainly from αT and a short stretch of residues from the Gi1 α subunit (αi1), which only weakly stimulates PDE activity. We then reinstated the αT residues by systematically replacing the corresponding αi1 residues within αT* with the aim of fully restoring PDE stimulatory activity. These experiments revealed that the αG/α4 loop and a phenylalanine residue at position 283 are essential for conferring the αT* subunit with full PDE stimulatory capability. We further demonstrated that this same region and amino acid within the α subunit of the Gs protein (αs) are necessary for full adenylyl cyclase activation. These findings highlight the importance of the αG/α4 loop and of an essential phenylalanine residue within this region on Gα subunits αT and αs as being pivotal for their selective and optimal stimulation of effector activity.

P3-209: Pitavastatin decreases tau levels via the inactivation of Rho family small G proteins

2011 ◽  
Vol 7 ◽  
pp. S583-S583
Author(s):  
Tadanori Hamano ◽  
Shu-Hui Yen ◽  
Tania Gendron ◽  
Li-wen Ko ◽  
Norimichi Shirafuji ◽  
...  
Keyword(s):  
G Proteins ◽  
Rho Family ◽  
Small G Proteins
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