Research Focus
Scaffold proteins dictate Rho GTPase-signaling specificity

https://doi.org/10.1016/j.tibs.2005.06.006Get rights and content

Given the numerous mechanisms that regulate the activity of Rho GTPases and the multiple effectors for Rho proteins, how is specificity achieved when transducing signals via Rho GTPase-regulated molecular networks? The finding that the scaffold protein hCNK1 links Rho guanine-nucleotide-exchange factors and Rho to JNK (c-Jun N-terminal kinase), while limiting stress-fiber formation and serum-response-factor activation, suggests that scaffold proteins govern the selection of signal outputs, thus helping to solve the Rho GTPase-signaling puzzle.

Section snippets

Rho-GTPase signaling networks

The Rho family of small GTPases, including RhoA, Rac1 and Cdc42, control numerous cellular processes ranging from the regulation of the actin-based cytoskeleton, cell morphology and motility, to nuclear gene expression, and normal and aberrant cell growth. They function as molecular switches that are inactive when bound to GDP, often in association with GDP-dissociation inhibitors, and are active when GDP is exchanged for GTP upon interaction with their specific guanine-nucleotide-exchange

Rho GTPases regulate the cytoskeleton and gene expression

In the early 1990s, Rho GTPases emerged as master regulators of the spatio-temporal organization of intracellular pools of polymerized actin [1]. Surprisingly, two Rho family members, Rac and Cdc42, were later shown to regulate gene expression by activating c-Jun N-terminal kinase (JNK), which is a member of the mitogen-activated protein kinase (MAPK) group of proline-targeted serine/threonine protein kinases [5]. These two events seemed to be highly inter-related, as constitutively activate

hCNK1 as a scaffold for Rho-initiated pathways

Whereas Rac and Cdc42 regulate nuclear events via JNK and p38, RhoA can stimulate expression from the c-fos serum-response element (SRE) by a MAPK-independent biochemical route 13, 14. This pathway involves the Rho-induced polymerization of actin into stress fibers, which ultimately results in the enhanced transcriptional activity of the serum-response factor (SRF) bound to the SRE 13, 14 (Figure 2). However, recent evidence indicates that Rho can also control the activity of MAPK cascades,

Concluding remarks

The emerging notion from the studies highlighted here is that the activation of Rho GTPases can lead to distinct biochemical and biological responses depending on the nature of the intervening GEFs and the ability of these GEFs to interact with different scaffold proteins. Thus, scaffold proteins might function as key signal organizers that determine the specificity of target selection by Rho GTPases in a spatial-temporal manner to favor the activation of a distinct subset of downstream

Cited by (40)

  • Expression pattern and function of tyrosine receptor kinase B isoforms in rat mesenteric arterial smooth muscle cells

    2015, Biochemical and Biophysical Research Communications
    Citation Excerpt :

    It is known that transcription factors to induce α-SMA protein involve activator protein 1, serum response factor (SRF), and c-Jun. It was reported that ROCK mediates activation of c-Jun and SRF via phosphorylation of JNK [18]. Therefore, it seems likely that TrkB T1 gene knockdown inhibits α-SMA expression by inactivating JNK/c-Jun-SRF pathway via preventing the activation of ROCK.

  • Unusual biophysics of intrinsically disordered proteins

    2013, Biochimica et Biophysica Acta - Proteins and Proteomics
  • Deciphering the molecular and functional basis of Dbl family proteins: A novel systematic approach toward classification of selective activation of the Rho family proteins

    2013, Journal of Biological Chemistry
    Citation Excerpt :

    Little is known about the modulation of the specificity and activity of Dbl proteins. Scaffolding proteins and post-translational modifications of bi- or oligo-specific Dbl proteins are possible integrating mechanisms to shift their specificity toward one or the other substrate Rho protein (76). Ccpg1, a regulatory scaffold protein, has been shown to shift the Dbs specificity toward activation of Cdc42 but not RhoA (77).

  • Modularity and functional plasticity of scaffold proteins as p(l)acemakers in cell signaling

    2012, Cellular Signalling
    Citation Excerpt :

    Furthermore, CNK1 can also cooperate with Rac to activate JNK, suggesting that CNK1 might interact with yet an unidentified RacGEF. Such versatility of CNK1 should therefore help integrate the signaling from different Rho GTPases to the JNK pathway [8]. Interestingly, functional crosstalk between ERK and Rho has also been report for the MP1 scaffold whereby ERK activation by PAK1 is linked to inhibition of Rho/Rho kinase, leading to turnover of focal adhesion for cell spreading [56].

  • S-nitrosylation-regulated GPCR signaling

    2012, Biochimica et Biophysica Acta - General Subjects
View all citing articles on Scopus
View full text