Somlyo, Andrew P., and Avril V. Somlyo. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol Rev 83: 1325-1358, 2003; 10.1152...

https://www.physiology.org/doi/pdf/10.1152/physrev.00023.2003

Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase

Guanine nucleotide-exchange factors (GEFs) are directly responsible for the activation of Rho-family GTPases in response to diverse extracellular stimuli, and ultimately regulate numerous cellular responses such as proliferation, differentiation and movement. With 69 distinct homologues, Dbl-related GEFs represent the largest family of direct activators of Rho GTPases in humans, and they activate Rho GTPases within particular spatio-temporal contexts. The failure to do so can have significant consequences and is reflected in the aberrant function of Dbl-family GEFs in some human diseases.

GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors

The RAS oncogenes were identified almost 20 years ago. Since then, we have learnt that they are members of a large family of small GTPases that bind GTP and hydrolyse it to GDP. This is then exchanged for GTP and the cycle is repeated. The switching between these two states regulates a wide range of cellular processes. A branch of the RAS family--the RHO proteins--is also involved in cancer, but what is the role of these proteins and would they make good therapeutic targets?

RHO-GTPases and cancer.

Chromosome aberrations, in particular translocations and their corresponding gene fusions, have an important role in the initial steps of tumorigenesis; at present, 358 gene fusions involving 337 different genes have been identified. An increasing number of gene fusions are being recognized as important diagnostic and prognostic parameters in malignant haematological disorders and childhood sarcomas. The biological and clinical impact of gene fusions in the more common solid tumour types has been less appreciated. However, an analysis of available data shows that gene fusions occur in all malignancies, and that they account for 20% of human cancer morbidity. With the advent of new and powerful investigative tools that enable the detection of cytogenetically cryptic rearrangements, this proportion is likely to increase substantially.

The impact of translocations and gene fusions on cancer causation

Rho GTPases control many aspects of cell behavior through the regulation of multiple signal transduction pathways (Van Aelst and D’Souza-Schorey 1997; Hall 1998). Rho, Rac, and Cdc42 were first recognized in the early 1990s for their unique ability to induce specific filamentous actin structures in fibroblasts; stress fibers, lamellipodia/membrane ruffles, and filopodia, respectively (Hall 1998). Over the intervening years, evidence has accumulated to show that in all eukaryotic cells, Rho GTPases are involved in most, if not all, actin-dependent processes such as those involved in migration, adhesion, morphogenesis, axon guidance, and phagocytosis (Kaibuchi et al. 1999; Chimini and Chavrier 2000; Luo 2000). In addition to their well-established roles in controlling the actin cytoskeleton, Rho GTPases regulate the microtubule cytoskeleton, cell polarity, gene expression, cell cycle progression, and membrane transport pathways (Van Aelst and D’Souza-Schorey 1997; Daub et al. 2001; Etienne-Manneville and Hall 2001). With such a prominent role in so many aspects of cell biology, it is not surprising that they are themselves highly regulated. Like all GTPases, Rho proteins act as binary switches by cycling between an inactive (GDP-bound) and an active (GTP-bound) conformational state (Fig. 1; Van Aelst and D’Souza-Schorey 1997). The cell controls this switch by regulating the interconversion and accessibility of these two forms in a variety of ways. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, which is then capable of recognizing downstream targets, or effector proteins. GTPase activating proteins (GAPs) accelerate the intrinsic GTPase activity of Rho family members to inactivate the switch. Finally, guanine nucleotide dissociation inhibitors (GDIs) interact with the prenylated, GDP-bound form to control cycling between membranes and cytosol. In theory, activation of a Rho GTPase could occur through stimulation of a GEF or inhibition of a GAP. In practice, however, all the evidence points to GEFs being the critical mediators of Rho GTPase activation, and this paper reviews our present understanding of how they do this. Structural features

/pdf/guanine-nucleotide-exchange-factors-for-rho-gtpases-turning-7l5hsifukr.pdf

Guanine nucleotide exchange factors for Rho GTPases: turning on the switch

We have identified a gene at 11q23, telomeric to MLL, that encodes a guanine nucleotide exchange factor (GEF). This gene is transcribed into a 9.5-kb mRNA containing a 4.6-kb ORF. By Northern analysis, it was found to be expressed in all human tissues examined including peripheral blood leukocytes, spleen, prostate, testis, ovary, small intestine, colon, and minimally in thymus. Analysis of the predicted protein sequence indicates that it has strong homology to several members of the family of Rho GEFs that includes such oncogenes as Dbl, Vav, Tiam, and Bcr. A patient with primary acute myeloid leukemia (AML) and a karyotype of 51,XY,+8,+19,+3mar was found to have the 5′ end of MLL at exon 6 fused in-frame with the 3′ end of almost the entire ORF of this gene, which we named LARG for leukemia-associated Rho GEF. Transcriptional orientation of both genes at 11q23 is from centromere to telomere, consistent with other data that suggest the MLL-LARG fusion resulted from an interstitial deletion rather than a balanced translocation. LARG does not appear to have any homology with other MLL partner genes reported thus far. Thus, LARG represents an additional member of the GEF family and a novel MLL fusion partner in acute myeloid leukemia.

https://www.pnas.org/content/pnas/97/5/2145.full.pdf

Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia.

Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.

Cyclosporine or steroids as an adjunct to plasma exchange in the treatment of immune-mediated thrombotic thrombocytopenic purpura

BACKGROUND
Financial toxicity is a growing problem in oncology, but no prior studies have prospectively measured the financial impact of cancer treatment in a diverse national cohort of newly diagnosed cancer patients. S1417CD was the first cooperative group-led multicenter prospective cohort study to evaluate financial hardship in metastatic colorectal cancer (mCRC) patients.


METHODS
Patients aged 18 years or older within 120 days of mCRC diagnosis completed quarterly questionnaires for 12 months. We estimated the cumulative incidence of major financial hardship (MFH), defined as 1 or more of increased debt, new loans from family and/or friends, selling or refinancing home, or 20% or more income decline. We evaluated the association between patient characteristics and MFH using multivariate cox regression and the association between MFH and quality of life using linear regression.


RESULTS
A total of 380 patients (median age = 59.9 years) were enrolled; 77.7% were White, 98.0% insured, and 56.5% had annual income of $50 000 or less. Cumulative incidence of MFH at 12 months was 71.3% (95% confidence interval = 65.7% to 76.1%). Age, race, marital status, and income (split at $50 000 per year) were not statistically significantly associated with MFH. However, income less than $100 000 and total assets less than $100 000 were both associated with greater MFH. MFH at 3 months was associated with decreased social functioning and quality of life at 6 months.


CONCLUSIONS
Nearly 3 out of 4 mCRC patients experienced MFH despite access to health insurance. These findings underscore the need for clinic and policy solutions that protect cancer patients from financial harm.

/pdf/s1417cd-a-prospective-multicenter-cooperative-group-led-13n8ue61.pdf

Peter J. Kourlas

Papers

Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia.

Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.

Cyclosporine or steroids as an adjunct to plasma exchange in the treatment of immune-mediated thrombotic thrombocytopenic purpura

S1417CD: A Prospective Multicenter Cooperative Group-Led Study of Financial Hardship in Metastatic Colorectal Cancer Patients.