The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex comp...

Rac1 regulates a wide variety of cellular processes. The polybasic region of the Rac1 C terminus functions both as a plasma membrane-targeting motif and a nuclear localization sequence (NLS). We show that a triproline N-terminal to the polybasic region contributes to the NLS, which is cryptic in the sense that it is strongly inhibited by geranylgeranylation of the adjacent cysteine. Subcellular...

To investigate the role of Rac1 for tumorigenesis, we generated inducible transgenic (Tg) mice that simultaneously express polyomavirus middle T antigen (mT) and Cre recombinase under the control of mouse mammary tumor virus long terminal repeat (MMTV-LTR) promoter (MMTV-LTR-tTA/mT-TRE-cre Tg). MMTV-LTR-tTA/mT- TRE-cre Tg mice formed tumors in the subcutaneous tissue and developed lung metastas...

Inhibitors of Apoptosis Proteins (IAPs) are well-studied E3 ubiquitin ligases predominantly known for regulation of apoptosis. We uncovered that IAPs can function as a direct E3 ubiquitin ligase of RhoGTPase Rac1. cIAP1 and XIAP directly conjugate polyubiquitin chains to Lysine 147 of activated Rac1 and target it for proteasomal degradation. Consistently, loss of these IAPs by various strategie...

The small GTPase Rac1 has been implicated in the formation and dissemination of tumours. Upon activation by guanine nucleotide exchange factors (GEFs), Rac1 associates with a variety of proteins in the cell thereby regulating various functions, including cell migration. However, activation of Rac1 can lead to opposing migratory phenotypes raising the possibility of exacerbating tumour progressi...

Macropinocytosis, a fluid-phase endocytosis, is a crucial pathway for antigen uptake and presentation in macrophages. We attempted to characterise the activation and deactivation of a small GTPase molecular switch, Rac1, in macropinocytosis using microscopic photo-manipulation. Expression of genetically encoded photoactivatable-Rac1 (PA-Rac1) in RAW264 macrophages enabled the local, reversible ...

Rac1 plays a key role in neurite outgrowth via reorganization of the actin cytoskeleton. The molecular mechanisms underlying Rac1-mediated actin dynamics in the cytosol and plasma membrane have been intensively studied, but the nuclear function of Rac1 in neurite outgrowth has not yet been addressed. Using subcellular fractionation and immunocytochemistry, we sought to explore the role of nucle...

Glutamatergic synapses switch from nonspiny synapses to become dendritic spines during early neuronal development. Here, we report that the lack of sufficient Rac1, a small RhoGTPase, contributes to the absence of spinogenesis in immature neurons. The overexpression of green fluorescence protein-tagged wild-type Rac1 initiated the formation of dendritic spines in cultured dissociated hippocampa...

Sustained forward migration through a fibrillar extracellular matrix requires localization of protrusive signals. Contact with fibronectin at the tip of a cell protrusion activates Rac1, and for linear migration it is necessary to dampen Rac1 activity in off-axial positions and redistribute Rac1 from non-protrusive membrane to the leading edge. Here, we identify interactions between coronin-1C ...

Yersinia pseudotuberculosis binds host cells and modulates the mammalian Rac1 guanosine triphosphatase (GTPase) at two levels. Activation of Rac1 results from integrin receptor engagement, while misregulation is promoted by translocation of YopE and YopT proteins into target cells. Little is known regarding how these various factors interplay to control Rac1 dynamics. To investigate these compe...