Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation

Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.

Rho GTPases in cell biology.

Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia

https://www.cell.com/trends/cell-biology/pdf/0962-8924(92)90174-L.pdf

The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors.

Cell Migration: A Physically Integrated Molecular Process

The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.

The small GTP-binding protein rac regulates growth factor-induced membrane ruffling

MORE than thirty small guanine nucleotide-binding proteins related to the ras-encoded oncoprotein, termed Ras or p21ras, are known1. They regulate many fundamental processes in all eukaryotic cells, such as growth, vesicle traffic and cytoskeletal organization. GTPase-activating proteins (GAPs) accelerate the intrinsic rate of GTP hydrolysis of Ras-related proteins, leading to down-regulation of the active GTP-bound form2. For p21ras two GAP proteins are known, rasGAP and the neurofibromatosis (NF1) gene product2–5. There is evidence that rasGAP may also be a target protein for regulation by Ras and be involved in downstream signalling6–8. We have purified a GAP protein for p21rho, which is involved in the regulation of the actin cytoskeleton9. Partial sequencing of rhoGAP reveals significant homology with the product of the bcr(breakpoint cluster region) gene, the translocation breakpoint in Philadelphia chromosome-positive chronic myeloid leukaemias. We show here that the carboxy-terminal domains of the bcr-encoded protein (Bcr) and of a Bcr-related protein, n-chimaerin, are both GAP proteins for the Ras-related GTP-binding protein, p21rac. This result suggests that Bcr could be a target for regulation by Rac and has important new implications for the role of bcr translocations in leukaemia.

Bcr encodes a GTPase-activating protein for p21rac.

Rho and Rac, two members of the Ras superfamily of guanosine triphosphate (GTP)-binding proteins, regulate a variety of signal transduction pathways in eukaryotic cells. Upon stimulation of phagocytic cells, Rac enhances the activity of the enzyme nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) oxidase, resulting in the production of superoxide radicals. Activation of the NADPH oxidase requires the assembly of a multimolecular complex at the plasma membrane consisting of two integral membrane proteins, gp91phox and p21phox, and two cytosolic proteins, p67phox and p47phox. Rac1 interacted directly with p67phox in a GTP-dependent manner. Modified forms of Rac with mutations in the effector site did not stimulate oxidase activity or bind to p67phox. Thus, p67phox appears to be the Rac effector protein in the NADPH oxidase complex.

https://science.sciencemag.org/content/sci/265/5171/531.full.pdf

Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity

Rac, a small GTPase in the ras superfamily, regulates at least two biological processes in animal cells: (i) the polymerization of actin and the assembly of integrin complexes to produce lamellipodia and ruffles; and (ii) the activity of an NADPH oxidase in phagocytic cells. NADPH oxidase activation is mediated through a rac effector protein, p67phox, and using chimeras made between rac and the closely related GTPase, rho, we have identified two distinct effector sites in rac, one N-terminal and one C-terminal, both of which are required for activation of p67phox. The same two effector sites are essential for rac-induced actin polymerization in fibroblasts. p65PAK, a ubiquitous serine/threonine kinase, interacts with rac at both the N- and C-terminal effector sites, but the GTPase-activating protein, bcr interacts with rac at a different region. This makes p65PAK, but not bcr, a candidate effector of rac-induced lamellipodium formation.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1995.tb00214.x

Dagmar Diekmann

Papers

The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.

The small GTP-binding protein rac regulates growth factor-induced membrane ruffling

Bcr encodes a GTPase-activating protein for p21rac.

Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity

Rac GTPase interacts with GAPs and target proteins through multiple effector sites.