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PubMed2005

Computational docking and solution x-ray scattering predict a membrane-interacting role for the histone domain of the Ras activator son of sevenless.

The Ras-specific nucleotide exchange factor son of sevenless (SOS) is a large, multidomain protein with complex regulation, including a Ras-dependent allosteric mechanism. The N-terminal segment of SOS, the histone domain, contains two histone folds, which is highly unusual for a cytoplasmic protein. Using a combination of computational docking, small-angle x-ray scattering, mutagenesis, and calorimetry, we show that the histone domain folds into the rest of SOS and docks onto a helical linker that connects the pleckstrin-homology (PH) and Dbl-homology (DH) domains of SOS to the catalytic domain. In this model, a positively charged surface region on the histone domain is positioned so as to provide a fourth potential anchorage site on the membrane for SOS in addition to the PH domain, the allosteric Ras molecule, and the C-terminal adapter-binding site. The histone domain in SOS interacts with the helical linker, using a region of the surface that in nucleosomes is involved in histone tetramerization. Adjacent surface elements on the histone domain that correspond to the DNA-binding surface of nucleosomes form the predicted interaction site with the membrane. The orientation and position of the histone domain in the SOS model implicates it as a potential mediator of membrane-dependent activation signals.

Allosteric Regulation↗
PubMed1995

Functional roles for the pleckstrin and Dbl homology regions in the Ras exchange factor Son-of-sevenless.

Activation of p21ras by receptor tyrosine kinases is thought to result from recruitment of guanine nucleotide exchange factors such as Son-of-sevenless (Sos) to plasma membrane receptor substrates via adaptor proteins such as Grb2. This hypothesis was tested in the present studies by evaluating the ability of truncation and deletion mutants of Drosophila (d)Sos to enhance [32P]GTP loading of p21ras when expressed in 32P-labeled COS or 293 cells. The dSos catalytic domain (residues 758-1125), expressed without the dSos NH2-terminal (residues 1-757) or adaptor-binding COOH-terminal (residues 1126-1596) regions, exhibits intrinsic exchange activity as evidenced by its rescue of mutant Saccharomyces cerevisiae deficient in endogenous GTP/GDP exchange activity. Here we show that this dSos catalytic domain fails to affect GTP p21ras levels when expressed in cultured mammalian cells unless the NH2-terminal domain is also present. Surprisingly, the COOH-terminal, adaptor binding domain of dSos was not sufficient to confer p21ras exchange activity to the Sos catalytic domain in these cells in the absence of the NH2-terminal domain. This function of promoting catalytic domain activity could be localized by mutational analysis to the pleckstrin and Dbl homology sequences located just NH2-terminal to the catalytic domain. The results demonstrate a functional role for these pleckstrin and Dbl domains within the dSos protein, and suggest the presence of unidentified cellular elements that interact with these domains and participate in the regulation of p21ras.

Amino Acid Sequence↗
PubMed1998

Differential interactions of the growth factor receptor-bound protein 2 N-SH3 domain with son of sevenless and dynamin. Potential role in the Ras-dependent signaling pathway.

In this paper, we show that the 36-45 surface-exposed sequence WYKAELNGKD of growth factor receptor-bound protein 2 (Grb2) N-SH3 domain inhibits the interaction between Grb2 and a 97-kDa protein identified as dynamin. Moreover, the peptide GPPPQVPSRPNR from dynamin also blocks the binding of dynamin to the proline-rich recognition platform of Grb2. Mutations in the 36-45 motif show that Glu-40 is critical for dynamin recognition. These observations were confirmed by immunoprecipitation experiments, carried out using ER 22 cells. It was also observed that the proline-rich peptide from dynamin was unable to dissociate the Grb2.Sos complex, whereas the proline-rich peptide from Son of sevenless (Sos) inhibited Grb2. dynamin interaction. A time-dependent stimulation of epidermal growth factor receptor overexpressing clone 22 (ER 22) cells by epidermal growth factor resulted in an immediate increase of the Grb2.Sos complex and a concomitant decrease in Grb2.dynamin. This suggests that the recruitment of Grb2.Sos to the membrane, triggered by epidermal growth factor stimulation, activates the Ras-dependent signaling and simultaneously enhances free dynamin levels, leading to both receptor internalization and endocytotic processes.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The Ras/Rac guanine nucleotide exchange factor mammalian Son-of-sevenless interacts with PACSIN 1/syndapin I, a regulator of endocytosis and the actin cytoskeleton.

Mammalian Son-of-sevenless (mSos) functions as a guanine nucleotide exchange factor for Ras and Rac, thus regulating signaling to mitogen-activated protein kinases and actin dynamics. In the current study, we have identified a new mSos-binding protein of 50 kDa (p50) that interacts with the mSos1 proline-rich domain. Mass spectrometry analysis and immunodepletion studies reveal p50 as PACSIN 1/syndapin I, a Src homology 3 domain-containing protein functioning in endocytosis and regulation of actin dynamics. In addition to PACSIN 1, which is neuron-specific, mSos also interacts with PACSIN 2, which is expressed in neuronal and nonneuronal tissues. PACSIN 2 shows enhanced binding to the mSos proline-rich domain in pull-down assays from brain extracts as compared with lung extracts, suggesting a tissue-specific regulation of the interaction. Proline to leucine mutations within the Src homology 3 domains of PACSIN 1 and 2 abolish their binding to mSos, demonstrating the specificity of the interactions. In situ, PACSIN 1 and mSos1 are co-expressed in growth cones and actin-rich filopodia in hippocampal and dorsal root ganglion neurons, and the two proteins co-immunoprecipitate from brain extracts. Moreover, epidermal growth factor treatment of COS-7 cells causes co-localization of PACSIN 1 and mSos1 in actin-rich membrane ruffles, and their interaction is regulated through epidermal growth factor-stimulated mSos1 phosphorylation. These data suggest that PACSINs may function with mSos1 in regulation of actin dynamics.

Actins↗
PubMed2000

Significance of the Grb2 and son of sevenless (Sos) proteins in human bladder cancer cell lines.

The epidermal growth factor (EGF) receptor has been suggested to have an important role in tumor initiation and progression of human bladder cancers. Grb2 protein, which is the downstream effector of the EGF receptor, acts as an adaptor protein between the EGF receptor and the Ras guanine-nucleotide exchange factor, son of sevenless (Sos) protein. Sos protein regulates the action of Ras protein by promoting the exchange of GDP for GTP. However, the significance of Grb2 and Sos proteins, which is related to EGF-triggered Ras activation, has not been elucidated in human bladder cancer. The aim of the present study is to clarify the significance of these proteins in human bladder cancer cell lines. In the present study, we used four human bladder cancer cell lines (T24, KU-7, UMUC-2, UMUC-6) and two kinds of cultured normal urothelial cells (HMKU-1, HMKU-2) isolated from patients with no malignancy. We examined the expression of EGF receptor, Grb2, and Sos proteins in these cells by Western blot analysis. Furthermore, the bladder cancer cell lines were subjected to sequence analysis to identify a point mutation in the c-H-ras gene at codon 12. There was no marked difference in the expression of the EGF receptor between human bladder cancer cell lines and cultured normal urothelial cells. On the other hand, expression of Grb2 and Sos proteins was substantially increased in all human bladder cancer cell lines examined in comparison with cultured normal urothelial cells, whether codon 12 of H-ras was mutated or not. These results suggest that the amplification of both Grb2 and SOS proteins plays an important role in the carcinogenesis of human bladder cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1992

The Son of sevenless gene product: a putative activator of Ras.

The Son of sevenless (Sos) gene functions in signaling pathways initiated by the sevenless and epidermal growth factor receptor tyrosine kinases. The Sos gene has now been isolated and sequenced. Its product is a 1595-amino acid protein similar to the CDC25 protein in Saccharomyces cerevisiae, a guanine nucleotide exchange factor that activates Ras. These results imply a role for the ras pathway in Drosophila neuronal development.

Amino Acid Sequence↗
PubMed1995

In vivo functional analysis of the Ras exchange factor son of sevenless.

The Son of sevenless (Sos) protein functions as a guanine nucleotide transfer factor for Ras and interacts with the receptor tyrosine kinase Sevenless through the protein Drk, a homolog of mammalian Grb2. In vivo structure-function analysis revealed that the amino terminus of Sos was essential for its function in flies. A molecule lacking the amino terminus was a potent dominant negative. In contrast, a Sos fragment lacking the Drk binding sites was functional and its activity was dependent on the presence of the Sevenless receptor. Furthermore, membrane localization of Sos was independent of Drk. A possible role for Drk as an activator of Sos is discussed and a Drk-independent interaction between Sos and Sevenless is proposed that is likely mediated by the pleckstrin homology domain within the amino terminus.

Animals↗
PubMed1993

Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes.

Signal transmission by insulin involves tyrosine phosphorylation of a major insulin receptor substrate (IRS-1) and exchange of Ras-bound guanosine diphosphate for guanosine triphosphate. Proteins containing Src homology 2 and 3 (SH2 and SH3) domains, such as the p85 regulatory subunit of phosphatidylinositol-3 kinase and growth factor receptor-bound protein 2 (GRB2), bind tyrosine phosphate sites on IRS-1 through their SH2 regions. Such complexes in COS cells were found to contain the heterologously expressed putative guanine nucleotide exchange factor encoded by the Drosophila son of sevenless gene (dSos). Thus, GRB2, p85, or other proteins with SH2-SH3 adapter sequences may link Sos proteins to IRS-1 signaling complexes as part of the mechanism by which insulin activates Ras.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Disassembly of Son-of-sevenless proteins from Grb2 during p21ras desensitization by insulin.

Insulin receptor signaling acutely stimulates GTP loading of p21ras, apparently by mobilizing complexes of Grb2 and the guanine nucleotide exchangers Son-of-sevenless (Sos) 1 and 2 to associate with tyrosine-phosphorylated proteins in the plasma membrane. Here we show that in 32P-labeled 3T3-L1 adipocytes the elevated cellular concentrations of [32P]GTP-bound p21ras in response to insulin return to near basal levels after 20-30 min of hormone stimulation, while insulin receptors remain activated. Lysates of such desensitized cells were quantitatively immunoprecipitated with an antiserum recognizing both Sos1 and Sos2 proteins or a specific anti-Sos2 antiserum. Immunoblot analysis of these precipitates revealed that insulin causes a marked hyperphosphorylation of Sos1 and a 50% decrease in Grb2 associated with Sos proteins under these conditions. Similarly, anti-Grb2 immunoprecipitates of such lysates revealed the presence of decreased Sos1 protein due to insulin action. The disassembly of Grb2 from Sos proteins slightly precedes the time course of p21ras deactivation in response to insulin. These data are consistent with the hypothesis that the dissociation of Grb2 from Sos proteins caused by insulin in 3T3-L1 cells mediates p21ras deactivation and desensitization.

3T3 Cells↗
PubMed1994

Phosphorylation of the Ras nucleotide exchange factor son of sevenless by mitogen-activated protein kinase.

Son of sevenless-1 and -2 (Sos-1 and -2) are guanosine nucleotide exchange factors implicated in the activation of Ras by both the insulin and epidermal growth factor signal transduction pathways. Ras appears to function by initiating the activation of cellular protein kinases including mitogen-activated protein (MAP) kinases. Sos proteins contain numerous sequences in their carboxyl-terminal regions which correspond to consensus sites for MAP kinase phosphorylation. To examine whether these sites are substrates for MAP kinases, the cDNA encoding Drosophila Sos (dSos) was tagged with sequences encoding the major antigenic epitope of the influenza virus hemagglutinin (HA) to create a dSosHA fusion construct. dSosHA was transiently expressed in COS-1 cells and immunoprecipitated with anti-HA antibodies. When immune complexes were incubated with purified MAP kinase and [gamma-32P]ATP, a phosphorylated band of 180 kDa was observed when analyzed by SDS-polyacrylamide gel electrophoresis. This band was not present in immunoprecipitations from cells transfected with vector alone. No phosphorylation of the 180 kDa band was seen when immunoprecipitates were incubated with [gamma-32P]ATP in the absence of MAP kinase. Two dimensional analysis of tryptic peptides from dSosHA phosphorylated by MAP kinase in vitro revealed two major phosphorylated species that were also found in dSosHA isolated from COS-1 cells labeled with 32Pi. These results are consistent with the hypothesis that a feedback loop exists wherein growth factor-activated MAP kinases phosphorylate and regulate Sos proteins.

Adenosine Triphosphate↗
PubMed1996

An 8-year follow-up of 450 sons of alcoholic and control subjects.

BACKGROUND: Between 1978 and 1988, 453 sons (age range, 18-29 years) of alcoholic and control subject were evaluated for their level of reaction (LR) to alcohol. This article presents the results of the 8.2-year follow-up of 450 of these men. The three goals were (1) to attempt to replicate results of the follow-up of the first 223 subjects, (2) to evaluate the potential impact of the quantity and frequency of drinking at the time of the original study on the relationship between LR and alcoholic outcome (ALC), and, most importantly, (3) to test if the relationship between family history (FH) and ALC might be mediated by LR in a subset of the sample. METHODS: Face-to-face structured follow-up interviews were carried out with the subjects and separately with an additional informant, and blood samples, as well as urine specimens, were obtained for determination of state markers of heavy drinking and drug toxicology screens. RESULTS: First, the rate of development of DSM-III-R abuse and dependence on alcohol was 14.1% and 28.6%, respectively, for family history positive (FHP) subjects, compared with 6.6% and 10.8%, respectively, for family history negative (FHN) men. Second, neither consideration of the quantity nor the frequency of drinking at the time of the original study, nor their combination, effectively diminished the relationships between LR and ALC. Third, among men who drank and demonstrated the 15% highest and lowest scores of LR at about the age of 20 years (ie, 30% of the relevant population), the correlation between FH and ALC was greatly reduced when LR was considered, but the correlation between LR and ALC was not greatly diminished when the impact of FH was evaluated. CONCLUSIONS: In this sample of moderately functional white men, the development of alcoholism occurred in relationship to an FH of alcoholism, but alcohol abuse or dependence was unrelated to prior psychiatric disorders. For this group, LR at the age of 20 years was associated with future alcoholism in a manner that was independent of the drinking practices at the time of the original study. At least among those men with clearly high and low LR scores, these data are consistent with the conclusion that LR might be a mediator of the alcoholism risk.

Adolescent↗
PubMed1981

Hairy cell leukemia in father and son.

A father and son hairy cell leukemia are identified on the basis of tartrate-resistant acid-phosphatase-positive hairy cells and diagnostic bone core biopsies. Personal interviews of the two patients revealed no evidence of consanguinity, primary immune deficiency, or common medication use. HLA typing revealed both patients to be A1,3 and B8,14.

Acid Phosphatase↗
PubMed1986

Robin sequence and oligodactyly in mother and son.

A combination of the Robin sequence with pre- and postaxial oligodactyly was observed in a mother and her son. This familial association has not been reported before and probably represents a previously unrecognized heritable malformation syndrome.

Abnormalities, Multiple↗
PubMed1987

Unilateral carpal bone deformity in mother and son.

We report on a mother and son with unilateral absence of most of the proximal carpal bones, dysplasia of the distal row of carpal bones, and deformity of the forearm. Although carpal bone dysplasia has been reported in several congenital or progressive disorders, unilateral involvement with lack of progression makes this a distinct entity.

Abnormalities, Multiple↗
PubMed1988

Cryptomicrotia and short, stubby fingers with excess fingertip arch patterns in a mother and son.

We describe a malformation syndrome of bilateral cryptomicrotia, brachytelomesophalangy, hypoplastic toe nails, and excess fingertip arch patterns in a chromosomally and mentally normal mother and son. Familial occurrence of this malformation complex has not been described previously and the manifestations of the patients do not correspond to those of any known malformation syndromes. The disorder in this family may be attributable to the pleiotropic effect of an autosomal or an X-linked dominant gene.

Abnormalities, Multiple↗
PubMed1991

Crossed polydactyly type I in a mother and son: an autosomal dominant trait?

In a Japanese family, a propositus and his mother had crossed polydactyly type I. A maternal grandaunt also had preaxial polydactyly of the feet. The findings that both of the mother and son had the identical type of polydactyly are consistent with an autosomal dominant inheritance with variable expressivity. Other explanations include X-linked recessive inheritance, polygenic inheritance, and a chance occurrence of the 2 different kinds of polydactyly.

Adult↗