Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells

Hajdo-Milašinović, Amra; Ellenbroek, Saskia I.J.; Es, Saskia van; Vaart, Babet van der; Collard, John G.

doi:10.1242/jcs.03364

Cited by 58 publications

(68 citation statements)

References 61 publications

(58 reference statements)

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“…The absence of ERa co-regulatory activity for RAC1 versus RAC3 is another example of the previously observed opposing effects of these two highly homologous proteins (Hajdo-Milasinovic´et al, 2007). In the current study, this difference was mapped to RAC3 S151, which corresponds to A151 in RAC1 (Figure 3).…”

Section: Discussionsupporting

confidence: 46%

RAC3 is a pro-migratory co-activator of ERα

Walker

Zhang

et al. 2011

Oncogene

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Estrogen receptor alpha (ERa) is a ligand-dependent nuclear receptor that is important in breast cancer genesis, behavior and response to hormone-based therapies. A T7 phage display screen against full-length human ERa, coupled with genome-wide exon arrays, was used to identify RAC3 as a putative ERa co-regulator. RAC3 is a Rho family small GTPase that is associated with cytoskeletal rearrangement. We demonstrate a novel role for nuclear RAC3 as an ERa transcriptional activator, with prognostic implications for metastatic disease. Through in vitro and cell-based studies, RAC3 was shown to exist in a GTP-bound state and act as a ligand specific ERa co-activator of E2-induced transcription. Overexpression of RAC3 induced pro-growth and pro-migratory genes that resulted in increased migration of ERapositive breast cancer cells. Chemical inhibition and genetic knockdown of RAC3 antagonized E2-induced cell proliferation, cell migration and ERa mediated gene expression, indicating that RAC3 is necessary for full ERa transcriptional activity. In agreement with the molecular and cellular data, RAC3 overexpression in ERa-positive breast cancers correlated with a significant decrease in recurrence free survival and a significant increase in the odds ratio of metastasis. In conclusion, RAC3 is a novel ERa co-activator that promotes cell migration and has prognostic value for ERa-positive breast cancer metastasis. RAC3 may also be a useful therapeutic target for ERa-positive breast cancers.

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Section: Discussionsupporting

confidence: 46%

RAC3 is a pro-migratory co-activator of ERα

Walker

Zhang

et al. 2011

Oncogene

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“…Yet, signaling specificity has been, in several studies, clearly linked to the C-terminus of RhoGTPases, both in vitro as well as in vivo. [133][134][135] More recently, several studies have shown for Rac1 that there is a functional connection between the C-terminus and the effector domain in the N-terminus 15 and that some C-terminal interactions are influenced by nuclear import required binding of Karyopherin α2 to the Rac1 C-terminus as well as Rac1 activity, additional factors must control nuclear accumulation of activated Rac1. These may be Rac1 effector domains, but could also be the (mono-)ubiquitylation of Rac1.…”

Section: Discussionmentioning

confidence: 99%

The Rac1 hypervariable region in targeting and signaling

Lam

Hordijk

2013

Small GTPases

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“…Rac3 has not previously been studied in hemopoietic cells, largely because its expression is highest in neurons (Bolis et al, 2003). However, it has previously been shown to have an opposing effect to Rac1 in neuronal cell adhesion and differentiation (Hajdo-Milasinović et al, 2007). Knockdown of RhoGDI1 was recently reported to lead to reduced levels of RhoA, Rac1, and Cdc42 (Boulter et al, 2010).…”

Section: Rhoa Is Required For T Cell Temmentioning

confidence: 99%