Biomedical subjects

S D Podos

Publications and source records attributed to S D Podos.

4 recordsLinked to original sources

PubMed2001

The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis.

We identified Drosophila Smurf (DSmurf) as a negative regulator of signaling by the BMP2/4 ortholog DPP during embryonic dorsal-ventral patterning. DSmurf encodes a HECT domain ubiquitin-protein ligase, homologous to vertebrate Smurf1 and Smurf2, that binds the Smad1/5 ortholog MAD and likely promotes its proteolysis. The essential function of DSmurf is restricted to its action on the DPP pathway. DSmurf has two distinct, possibly mechanistically separate, functions in controlling DPP signaling. Prior to gastrulation, DSmurf mutations cause a spatial increase in the DPP gradient, as evidenced by ventrolateral expansion in expression domains of target genes representing all known signaling thresholds. After gastrulation, DSmurf mutations cause a temporal delay in downregulation of earlier DPP signals, resulting in a lethal defect in hindgut organogenesis.

Animals↗

PubMed1999

Morphogen gradients: new insights from DPP.

The Drosophila TGFbeta family member Decapentaplegic (DPP) has been proposed to function as a morphogen to pattern cell fields in a number of developmental contexts. A series of recent reports add significantly to our knowledge of the mechanisms of DPP-gradient formation and interpretation. These reports identity additional genes and genetic circuitry necessary for this patterning system, and they highlight variations that might reflect developmental constraints within individual target cell fields.

Animals↗

PubMed1998

The Drosophila Medea gene is required downstream of dpp and encodes a functional homolog of human Smad4.

The Transforming Growth Factor-beta superfamily member decapentaplegic (dpp) acts as an extracellular morphogen to pattern the embryonic ectoderm of the Drosophila embryo. To identify components of the dpp signaling pathway, we screened for mutations that act as dominant maternal enhancers of a weak allele of the dpp target gene zerknŁllt. In this screen, we recovered new alleles of the Mothers against dpp (Mad) and Medea genes. Phenotypic analysis of the new Medea mutations indicates that Medea, like Mad, is required for both embryonic and imaginal disc patterning. Genetic analysis suggests that Medea may have two independently mutable functions in patterning the embryonic ectoderm. Complete elimination of maternal and zygotic Medea activity in the early embryo results in a ventralized phenotype identical to that of null dpp mutants, indicating that Medea is required for all dpp-dependent signaling in embryonic dorsal-ventral patterning. Injection of mRNAs encoding DPP or a constitutively activated form of the DPP receptor, Thick veins, into embryos lacking all Medea activity failed to induce formation of any dorsal cell fates, demonstrating that Medea acts downstream of the thick veins receptor. We cloned Medea and found that it encodes a protein with striking sequence similarity to human SMAD4. Moreover, injection of human SMAD4 mRNA into embryos lacking all Medea activity conferred phenotypic rescue of the dorsal-ventral pattern, demonstrating conservation of function between the two gene products.

Amino Acid Sequence↗

PubMed1994

LDLC encodes a brefeldin A-sensitive, peripheral Golgi protein required for normal Golgi function.

Two genetically distinct classes of low density lipoprotein (LDL) receptor-deficient Chinese hamster ovary cell mutants, ldlB and ldlC, exhibit nearly identical pleiotropic defects in multiple medial and trans Golgi-associated processes (Kingsley, D., K. F. Kozarsky, M. Segal, and M. Krieger. 1986. J. Cell Biol. 102:1576-1585). In these mutants, the synthesis of virtually all N- and O-linked glycoproteins and of the major lipid-linked oligosaccharides is abnormal. The abnormal glycosylation of LDL receptors in ldlB and ldlC cells results in their dramatically reduced stability and thus very low LDL receptor activity. We have cloned and sequenced a human cDNA (LDLC) which corrects the mutant phenotypes of ldlC, but not ldlB, cells. Unlike wild-type CHO or ldlB cells, ldlC cells had virtually no detectable endogenous LDLC mRNA, indicating that LDLC is likely to be the normal human homologue of the defective gene in ldlC cells. The predicted sequence of the human LDLC protein (ldlCp, approximately 83 kD) is not similar to that of any known proteins, and contains no major common structural motifs such as transmembrane domains or an ER translocation signal sequence. We have also determined the sequence of the Caenorhabditis elegans ldlCp by cDNA cloning and sequencing. Its similarity to that of human ldlCp suggests that ldlCp mediates a well-conserved cellular function. Immunofluorescence studies with anti-ldlCp antibodies in mammalian cells established that ldlCp is a peripheral Golgi protein whose association with the Golgi is brefeldin A sensitive. In ldlB cells, ldlCp was expressed at normal levels; however, it was not associated with the Golgi. Thus, a combination of somatic cell and molecular genetics has identified a previously unrecognized protein, ldlCp, which is required for multiple Golgi functions and whose peripheral association with the Golgi is both LDLB dependent and brefeldin A sensitive.

Adaptor Proteins, Vesicular Transport↗