High impact information on phl

• Previous analyses have demonstrated that Ras1 (p21ras) operates upstream of the D-Raf (Raf1) serine/threonine kinase in this signaling pathway [1].
• Dsor1Su1 mapped on X chromosome significantly suppressed the D-raf mutant phenotypes, and the loss-of-function mutations of Dsor1 showed phenotypes similar to those of the D-raf null mutations [2].
• Repression requires the D-raf kinase and is associated with phosphorylation of bcd protein [3].
• D-raf, a Drosophila homolog of Raf-1, plays key roles in multiple signal transduction pathways [2].
• Such a process is in agreement with the finding that both tor and l(1)ph messenger RNAs are evenly distributed [4].

Biological context of phl

• Connector enhancer of KSR (CNK), an essential component of Drosophila receptor tyrosine kinase/mitogen-activated protein kinase pathways, regulates oppositely RAF function [5].
• Biochemical analysis of torso and D-raf during Drosophila embryogenesis: implications for terminal signal transduction [6].
• D-Raf is expressed throughout embryogenesis; however, the phosphorylation state of the protein changes during development [6].
• Embryos lacking Torso activity, however, show significant reductions in D-Raf protein expression rather than major alterations in the protein's phosphorylation state [6].
• Furthermore, combined deficiencies of D-Ras1 and D-Rap1 completely abolished expression of these genes, mimicking the phenotype observed in embryos lacking D-Raf [7].

Anatomical context of phl

• We also characterize the accumulation of maternal D-raf proteins in 0-2-hr embryos derived from females with germ cells lacking D-raf activity [8].
• We also find that mKSR1 associates with Raf-1 at the plasma membrane in a Ras-dependent manner, indicating the presence of a membrane-bound kinase signaling complex [9].
• Here we identify a novel family of Drosophila proteins, Nasrat and Polehole, that coat the oocyte surface and play two roles: They mediate assembly of the eggshell, and act in the Torso RTK signaling pathway that specifies the terminal regions of the embryo [10].
• Thus, we provide evidence that zygotic D-raf acts to specify cell fates in two distinct pathways that generate dorsoventral pattern within the ectoderm [11].
• However, in contrast to the dominant active mutant of Ki-Ras, which interacts with Raf-1, recruits it to the plasma membrane from the cytosol, and activates it, MAGUIN-1 neither activates Raf-1 nor recruits it to the plasma membrane [12].

Associations of phl with chemical compounds

• The D-raf gene product, which is required for Torso function, is identified as a 90-kDa protein with intrinsic serine/threonine kinase activity [6].
• Membrane-targeted D-raftor4021 showed the highest level of activity, followed by alanine-substituted D-rafS388A and N-terminal-truncated D-raf delta 445 [13].
• Association of membrane-associated guanylate kinase-interacting protein-1 with Raf-1 [12].

Physical interactions of phl

• We show that D-Rap1 binds D-Raf and activates ERKs in a GTP- and D-Raf-dependent manner [7].
• We also found that the D-STAT-binding site is required for injury-induced activation of the D-raf gene promoter [14].
• These findings suggest that mutant forms of D-raf may deplete the embryo of a positive activator and/or form inactive protein complexes that affect rescue of the Tor pathway [8].
• Cell surface proteins Nasrat and Polehole stabilize the Torso-like extracellular determinant in Drosophila oogenesis [10].

Regulatory relationships of phl

• Eight alleles of Dsor1 encoding a Drosophila homologue of mitogen-activated protein (MAP) kinase kinase were obtained as dominant suppressors of the MAP kinase kinase kinase D raf [15].
• Here we propose that D-STAT can participate in regulation of the mitogen-activated protein kinase cascade through D-raf gene activation [14].
• Unexpectedly, we also report that the C-terminal region of CNK contains a short bipartite element that strongly inhibits RAF catalytic function [16].
• Furthermore, half reduction of the D-raf gene dose suppressed this DREF-induced vein of increased width phenotype [17].

Other interactions of phl

• Here, we demonstrate that Hop requires the activity of the Raf pathway to promote the activation response of larval plasmatocytes, and provide evidence to suggest that the Hop and D-Raf proteins physically interact [18].
• Here, we present biochemical and genetic evidence that D-Rap1, the Drosophila homolog of Rap1, can activate D-Raf and ERK [7].
• This signaling pathway is mediated by the serine/threonine kinase D-raf and a protein tyrosine phosphatase corkscrew (csw) [19].
• The Drosophila raf (D-raf) gene promoter contains a recognition consensus sequence for Drosophila STAT (D-STAT) [14].
• By analogy to catalytically impaired, but conformationally active B-RAF oncogenic mutants, we discuss the possibility that KSR represents a natural allosteric inducer of RAF catalytic function [20].

Analytical, diagnostic and therapeutic context of phl

• As assessed by DNase I footprinting and promoter dissection experiments, two of these elements are potential regulatory targets of Raf-1-activated transcription factors [21].
• The most closely related to v-raf was mapped by in situ hybridization to position 2F5-6 (Draf-1) on the X chromosome, whereas the other raf-related gene (Draf-2) was found at position 43A2-5 on chromosome 2 [22].
• We demonstrate, using a series of mutations in the signal transducers Corkscrew/SHP-2 and D-Raf, that quantitative variations in the magnitude of MAPK activity trigger both qualitatively and quantitatively distinct transcriptional responses [23].

References