In this issue of Small GTPases

Syndecan-4 promotes healing

The presence of fibronectin, leaked after wounding, results in the recruitment of fibroblasts, a key component in the healing process. The migration of fibroblasts is directed by syndecan-4, via the small GTPases Rac1, RhoA and RhoG. In this letter to the editor, Rebecca Brooks, Rosalind Williamson and Mark Bass uncover yet another GTPase, Arf6, important for fibroblast migration in response to fibronectin. The authors illustrate how each of these GTPases are regulated by syndecan-4, and yet remain independent of each other. These findings suggest that the coordinating center for migratory cues start with syndecan-4.

Signaling at the Golgi

Small GTPases are responsible for the regulation of a host of homeostatic processes, placing the understanding of small GTPase signaling high on the list of priorities. Crosstalk among the many small GTPase families, however, muddies the waters. In this review, Baschieri and Farhan focus on signaling at the Golgi apparatus, a hub for several of these molecules. The authors also highlight other recent works that address crosstalk and provide an overview on available methods for investigating crosstalk between small GTPase families.

Lulu proteins tighten actomyosin belt

During morphogenesis, epithelial cells must concurrently alter their shape in a dynamic manner. Apical construction is one way that a cell can change shape and this process is thought to be driven by myosin-II-dependent forces that mainly arise from the actomyosin belt. The mechanisms that regulate this belt are poorly understood. In this commentary, Nakajima and Tanoue describe their recently identified factors—Lulu1 and Lulu2—as regulators of the actomyosin belt, with a focus on the Lulu2-p114RhoGEF system.

Don’t forget about Ras-related members

Classical Ras subfamily members are well studied when it comes to their involvement in human cancers. Ras-related subfamily members, however, fall behind when it comes to cancer research, even though evidence points to one of its members (TC21) having a strong effect on cell transformation. In this commentary, Alarcón and Martínez-Martín discuss TC21 involvement in t-cell antigen receptor internalization and trogocytosis. The authors suggest a functional specialization that may exist between classical Ras and Ras-related subfamilies.

Curbing Rac1 activity with HACE1

One way to regulate signal transduction pathways is via ubiquitin-mediated targeting of active proteins to the proteasome for degradation. Dampening Rho GTPase mediated signaling is no exception. In this commentary, Mettouchi and Lemichez review their findings on the involvement of E3 ubiquitin-ligase, HACE1, in the catalyzation of the ubquitylation of GTP-bound Rac1. In fact, the authors propose the some pathogenic bacteria are able to hijack HACE1’s ability to limit Rac1 activity for their own gain.

Inept Rab/OCLR1 binding and Lowe syndrome

Mutations in the Rab effector protein, OCRL1, are responsible for renal dysfunction and the impaired development of the eye and nervous system in Lowe syndrome. In this commentary, Hagemann et al. review their recent biophysical and structural work on the Rab binding domain of OCLR1 along with the high binding affinity Rab GTPase, Rab8. Understanding OCLR1/Rab binding properties could reveal mechanisms that lead to Lowe syndrome.

Rags to autophagy

Many factors are involved in the activation of mammalian target of rapamycin (mTOR), the master regulator of protein metabolism. Recent research has emerged implicating Rag GTPases, members of the Ras super family, as playing a role in the mTOR pathway. In this commentary, Narita and Inoki describe how Rag GTPases, along with Ragulator, are involved in amino acid-mediated mTOR regulation. The authors also describe a unique cytoplasmic compartment, or the TOR-autophagy spatial coupling compartment (TASCC), and how it sheds light on the functional relevance of Rag-mediated association between mTOR and lysosomes, critical for the amino acid activation of mTOR.

Effective translocation of melanoblasts requires Rac1

Cancer metastasis is similar in many ways to the process of embryonic development. Indeed, how cancer cells are able to take control may lie with their abilities to reactivate embryonic developmental pathways. In this commentary, Li and Machesky discuss their recent findings derived from studying the migration of melanoblasts. Melanoblasts have an interesting pattern of Rac1 dependent and independent migration,, depending on the movement. Rac1 is required to set the pace of the formation of actin-based protrusions that allows for translocation within the epidermis. These studies may reveal new insights in how Rac1 is involved in normal embryogenesis and also how it is involved in metastasis.

Oncogenic RAS-induced ROS plus MTH1 promotes tumors

The RAS oncogene is an important promoter for many pro-tumor activities. Many of these activities are driven by oncogenic RAS-induced reactive oxygen species (ROS). Interestingly, the induction of ROS activity also leads to tumor suppression. In this commentary, Priuamvada Rai discusses recent evidence for the tumor-promoting roles of human MutT Homolog 1 (MTH1) in RAS-induced ROS. This research points to potential new avenues of therapy by specifically targeting MTH1 in RAS-transformed tumor cells that could result in proliferative defects and possible tumor cytotoxicity.

Cancer type matters for RalA and RalB

Downstream effector pathways of mutationally activated K-Ras, Raf and PI3K, are relatively well studied. Despite its critical role in cancer biology, the Ral guanine nucleotide exchange factor (RalGEF) activation of RalA and RalB small GTPases, however, remains poorly understood. Recent evidence provides a role for the RalGEF pathway in tumorgenesis and metastasis of PDAC tumor cells. Using CRC tumor lines, Martin and Der discuss the role of RalGEF, specifically the antagonistic roles of RalA and RalB. These differences in Ral function highlight the importance of distinguishing cancer cell type in order to use a targeted therapeutic approach.

IAP regulation of Rac1

Depleting Inhibitors of Apoptosis Proteins (IAPs) sensitizes tumor cells to chemotherapeutic drugs, a welcomed outcome in the fight against cancer. In this commentary, Oberoi-Khanuja and Rajalingam share findings that IAPs are able to function as an E3 ubiquitin ligase of RhoGTPase Rac1, an evolutionary conserved role. Understanding the roles of IAPs in tumor cell migration and invasion should prove to be another weapon against cancer.