We describe a system of hybrid dysgenesis in Drosophila virilis in which at least four unrelated transposable elements are all mobilized following a dysgenic cross. The data are largely consistent with the superposition of at least three different systems of hybrid dysgenesis, each repressing a different transposable element, which break down following the hybrid cross, possibly because they share a common pathway in the host. The data are also consistent with a mechanism in which mobilization of a single element triggers that of others, perhaps through chromosome breakage. The mobilization of multiple, unrelated elements in hybrid dysgenesis is reminiscent of McClintock's evidence [McClintock, B. (1955) Brookhaven Symp. Biol. 8, 58-74] for simultaneous mobilization of different transposable elements in maize.

EGL-15 is a fibroblast growth factor receptor in the nematode Caenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated both let-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophila and mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways in Drosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15.Receptor tyrosine kinases (RTKs) play critical roles in translating cues gathered from the extracellular environment into biological responses such as cellular differentiation, proliferation, and migration events. RTKs such as the platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) receptors define a family of single-pass transmembrane proteins with an intracellular tyrosine kinase domain (51). Binding of growth factor to the extracellular portions of these receptors promotes receptor dimerization and activation of the intracellular tyrosine kinase domain (43). Receptor activation leads to receptor autophosphorylation as well as phosphorylation of cytoplasmic signaling proteins. Specific phosphotyrosine sites on the receptor can serve to propagate signaling by recruiting Src homology domain 2 (SH2) and PTB domain-containing signaling proteins directly to the activated receptor (37, 38). For example, many RTKs can signal to the RAS/mitogen-activated protein kinase (MAPK) cascade via direct recruitment of the SH2/SH3 domain-containing adaptor protein GRB2 in complex with SOS, the guanine nucleotide exchange factor for RAS (31). EGF and PDGF RTKs can utilize direct recruitment of the GRB2/ SOS complex to achieve RAS activation. This canonical pathway is well-conserved in Caenorhabditis elegans, Drosophila, and mammalian systems (37).There is compelling evidence that the RAS/MAPK signaling pathway plays an important role in signaling via FGF receptors (FGFRs) as well (32). However, unlike the EGF and PDGF receptors, FGFRs do not appear to recruit GRB2/SOS directly. Instead, mammalian FGFR-1 makes use of the m...

Growth factor receptor tyrosine kinases (RTKs), such as the fibroblast growth factor receptor (FGFR), play a major role in how cells communicate with their environment. FGFR signaling is crucial for normal development, and its misregulation in humans has been linked to developmental abnormalities and cancer. The precise molecular mechanisms by which FGFRs transduce extracellular signals to effect specific biologic responses is an area of intense research. Genetic analyses in model organisms have played a central role in our evolving understanding of these signal transduction cascades. Genetic studies in the nematode C. elegans have contributed to our knowledge of FGFR signaling by identifying genes involved in FGFR signal transduction and linking their gene products together into signaling modules. This review will describe FGFR-mediated signal transduction in C. elegans and focus on how these studies have contributed to our understanding of how FGFRs orchestrate the assembly of intracellular signaling pathways.

NCT01564251.

Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors. Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m (Arm A), then increased to 1,000 mg/m (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses. Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m Dose-limiting toxicities included thrombocytopenia ( = 5), neutropenia ( = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase ( = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (-mutated) and melanoma ( = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin. Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. .