Targeting and localized signalling by small GTPases.
Polarized cellular responses, for example, cell migration, require the co-ordinated assembly of signalling complexes at a particular subcellular location, such as the leading edge of cells. Small GTPases of the Ras superfamily play central roles in many (polarized) responses to growth factors, chemokines or integrin ligands. These small GTPases are functionally distinct, yet remarkably homologous in their primary sequence and especially in their effector domains. Therefore it has long been unclear how GTPase signalling specificity is regulated. Small GTPases carry a lipid anchor, in the context of a hypervariable region, which mediates membrane association. However, whereas the lipid has long been proposed to be the critical regulator of subcellular GTPase targeting, there is now increasing evidence that specific protein-protein interactions are important as well. This review discusses recent findings on GTPase targeting and proposes a revised model for GTPase signalling. In this model, the hypervariable domain acts in conjunction with the lipid tail to target the GTPase to specific membrane-associated protein complexes. Here, local GTPase activation occurs, leading to subsequent exposure of the effector domain, binding to effector proteins and the initiation of downstream signalling.
ten Klooster
Jean Paul
JP
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
Hordijk
Peter L
PL
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D020559:Monomeric GTP-Binding Proteins