Functional Roles for the Pleckstrin and Dbl Homology Regions in the Ras Exchange Factor Son-of-sevenless (*)

Activation of p21 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 [P]GTP loading of p21 when expressed in P-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 GTPp21 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 p21 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 p21.

• Publication year

  1995

• Venue

  Journal of Biological Chemistry

• Publication date

  1995-07-07

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/JBC.270.27.15954PMID 7608150
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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

  1995cited by this paper
• The Grb2 binding domain of mSos1 is not required for downstream signal transduction

  1995cited by this paper
• SH2/SH3 signaling proteins.

  1994cited by this paper
• Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate

  1994cited by this paper
• Structure of the pleckstrin homology domain from β-spectrin

  1994cited by this paper
• Prenylation of Ras proteins is required for efficient hSOS1-promoted guanine nucleotide exchange.

  1994cited by this paper
• Activators and effectors of ras p21 proteins.

  1994cited by this paper
• PHAS-I as a link between mitogen-activated protein kinase and translation initiation.

  1994cited by this paper
• Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway.

  1994cited by this paper
• Structure of the pleckstrin homology domain from beta-spectrin.

  1994cited by this paper
• Raf: the holy grail of Ras biology?

  1994cited by this paper
• Sequential protein kinase reactions controlling cell growth and differentiation.

  1994cited by this paper
• Binding of G protein beta gamma-subunits to pleckstrin homology domains.

  1994cited by this paper
• PH domain: the first anniversary.

  1994cited by this paper
• The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C.

  1994cited by this paper
• Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.

  1993cited by this paper
• Signalling through SH2 and SH3 domains.

  1993cited by this paper
• Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1

  1993cited by this paper
• Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation

  1993cited by this paper
• The PH domain: a common piece in the structural patchwork of signalling proteins.

  1993cited by this paper
• Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling

  1993cited by this paper
• The role of p21ras in receptor tyrosine kinase signaling.

  1993cited by this paper
• Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.

  1993cited by this paper
• The catalytic domain of the mouse sos1 gene product activates Ras proteins in vivo and in vitro.

  1993cited by this paper
• The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1

  1993cited by this paper
• Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes.

  1993cited by this paper
• The SH2/SH3 domain‐containing protein GRB2 interacts with tyrosine‐phosphorylated IRS1 and Shc: implications for insulin control of ras signalling.

  1993cited by this paper
• The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling.

  1992cited by this paper
• SH2 and SH3 domains: from structure to function.

  1992cited by this paper
• Preferential inhibition of the oncogenic form of RasH by mutations in the GAP binding/"effector" domain.

  1991cited by this paper
• Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme.

  1989cited by this paper
• The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway.

  1987cited by this paper
• The structure of an antigenic determinant in a protein.

  1984cited by this paper
• Roles of the CDC24 gene product in cellular morphogenesis during the Saccharomyces cerevisiae cell cycle

  1981cited by this paper
• A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.

  1976cited by this paper

• ALK and CD36 as new causing genes for hereditary gingival fibromatosisNew evidences of genetic heterogeneity of causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.

  2022cites this paper
• Clinics and genetic background of hereditary gingival fibromatosis

  2021cites this paper
• Targeting Son of Sevenless 1: The pacemaker of KRAS.

  2021cites this paper
• One-way membrane trafficking of SOS in receptor-triggered Ras activation

  2016cites this paper
• UvA-DARE ( Digital Academic Repository ) Signaling in vascular biology : The role of GTPases and GEFs in endothelial cell function

  2015cites this paper
• Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

  2013cites this paper
• Chapter 144 – Phospholipase D

  2010cites this paper
• Phosphatidic acid signaling regulation of Ras superfamily of small guanosine triphosphatases.

  2009cites this paper
• Many faces of Ras activation.

  2008cites this paper
• Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos

  2007cites this paper
• Grb2 is a negative modulator of the intrinsic Ras-GEF activity of hSos1.

  2006influential citation
• Ras-Gefs and Ras Gaps

  2006cites this paper
• Insulin and EGF Receptors Signaling Pathways Integrate the Ras and Rap

  2006cites this paper
• Positive and negative regulators of Ras in T cells

  2004cites this paper
• hSos1 contains a new amino-terminal regulatory motif with specific binding affinity for its pleckstrin homology domain.

  2002cites this paper
• hSos1 Contains a New Amino-terminal Regulatory Motif with Specific Binding Affinity for Its Pleckstrin Homology Domain*

  2002cites this paper
• A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1.

  2002cites this paper
• Structure-based Mutagenesis Reveals Distinct Functions for Ras Switch 1 and Switch 2 in Sos-catalyzed Guanine Nucleotide Exchange*

  2001cites this paper
• The Multisubstrate Adapter Gab1 Regulates Hepatocyte Growth Factor (Scatter Factor)–c-Met Signaling for Cell Survival and DNA Repair

  2001cites this paper
• Dictyostelium: an ideal organism for genetic dissection of Ras signalling networks.

  2001cites this paper
• The isoform-specific stretch of hSos1 defines a new Grb2-binding domain

  2000cites this paper
• The function of Ras proteins in Dictyostelium discoideum

  2000cites this paper
• The sevenless signaling pathway: variations of a common theme.

  2000cites this paper
• The endocytic protein intersectin is a major binding partner for the Ras exchange factor mSos1 in rat brain

  2000cites this paper
• Cytoskeleton and Small G Proteins

  1999cites this paper
• The N-terminal half of Cdc25 is essential for processing glucose signaling in Saccharomyces cerevisiae.

  1999cites this paper
• Isoform-specific insertion near the Grb2-binding domain modulates the intrinsic guanine nucleotide exchange activity of hSos1

  1999cites this paper
• Insulin-induced Desensitization of Extracellular Signal-regulated Kinase Activation Results from an Inhibition of Raf Activity Independent of Ras Activation and Dissociation of the Grb2-SOS Complex*

  1999cites this paper
• Insulin and EGF receptors integrate the Ras and Rap signaling pathways.

  1999cites this paper
• The DH protein family, exchange factors for Rho-like GTPases.

  1999cites this paper
• alphaPix stimulates p21-activated kinase activity through exchange factor-dependent and -independent mechanisms.

  1999cites this paper
• Interaction between Pleckstrin homology domains and G protein betagamma-subunits: analyses of kinetic parameters by a biosensor-based method.

  1999cites this paper
• Membrane-targeting of signalling molecules by SH2/SH3 domain-containing adaptor proteins.

  1999cites this paper
• αPix Stimulates p21-activated Kinase Activity through Exchange Factor-dependent and -independent Mechanisms*

  1999cites this paper
• Functional involvement of mSos in interleukin-3 and thrombin stimulation of the Ras, mitogen-activated protein kinase pathway in BaF3 murine hematopoietic cells.

  1998cites this paper
• Genetic analysis of sevenless tyrosine kinase signaling in Drosophila.

  1998cites this paper
• Protein kinase C: a paradigm for regulation of protein function by two membrane-targeting modules.

  1998cites this paper
• Protein Kinase D Activation by Mutations within Its Pleckstrin Homology Domain*

  1998cites this paper
• N Terminus of Sos1 Ras Exchange Factor: Critical Roles for the Dbl and Pleckstrin Homology Domains

  1998cites this paper
• Inhibition of mSOS-activity by binding of phosphatidylinositol 4,5-P2 to the mSOS pleckstrin homology domain

  1998cites this paper
• Regulation of Sos Activity by Intramolecular Interactions

  1998cites this paper
• Pleckstrin homology domains.

  1998cites this paper
• SH3 binding domains in the dopamine D4 receptor.

  1998cites this paper
• Activation of Ras and its downstream extracellular signal-regulated protein kinases by the CDC25 homology domain of mouse Son-of-sevenless 1 (mSos1)

  1998cites this paper
• Interferonγ Activation of Raf-1 Is Jak1-dependent and p21ras-independent*

  1998cites this paper
• Analysis of the Mechanism of Ras Activation: Mapping of Important Functional Domains of the Son of Sevenless Protein

  1998cites this paper
• Points of convergence between Ca2+ and Ras signalling pathways.

  1998cites this paper
• Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

  1998cites this paper
• Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos.

  1998cites this paper
• G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors.

  1997cites this paper
• Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for Sos1 in EGFR signaling and development.

  1997cites this paper
• Activation of the exchange factor Ras‐GRF by calcium requires an intact Dbl homology domain

  1997cites this paper
• Dbl family proteins.

  1997cites this paper
• EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2

  1997cites this paper
• Signal characteristics of G protein‐transactivated EGF receptor

  1997cites this paper
• Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor–MAP kinase–fos signalling pathway

  1997cites this paper
• A Comparative Analysis of the Phosphoinositide Binding Specificity of Pleckstrin Homology Domains*

  1997cites this paper
• The solution structure of the pleckstrin homology domain of mouse Son-of-sevenless 1 (mSos1).

  1997cites this paper
• Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors.

  1997cites this paper
• Cloning and characterization of the mouse homolog of the human A6 gene.

  1997cites this paper
• Isolation and molecular characterization of a gene from Drosophila melanogaster encoding a predicted Rho guanine nucleotide exchange factor

  1997cites this paper
• High Affinity Binding of the Pleckstrin Homology Domain of mSos1 to Phosphatidylinositol (4,5)-Bisphosphate*

  1997cites this paper
• The role of the PH domain in the signal‐dependent membrane targeting of Sos

  1997influential citation
• 21 G-protein-coupled receptors and their regulation

  1997cites this paper
• Specific role for the PH domain of dynamin‐1 in the regulation of rapid endocytosis in adrenal chromaffin cells

  1997influential citation
• The Solution Structure of the Pleckstrin Homology Domain of Human SOS1

  1997cites this paper
• Not all Shc's roads lead to Ras.

  1996cites this paper
• PH domains: diverse sequences with a common fold recruit signaling molecules to the cell surface.

  1996cites this paper
• G protein-coupled receptor kinase GRK2 is a phospholipid-dependent enzyme that can be conditionally activated by G protein betagamma subunits.

  1996cites this paper
• The Grb2-mSos1 Complex Binds Phosphopeptides with Higher Affinity than Grb2*

  1996cites this paper
• DOS, a novel pleckstrin homology domain-containing protein required for signal transduction between sevenless and Ras1 in Drosophila.

  1996cites this paper
• Interplay between Ras‐related and heterotrimeric GTP binding proteins: lifestyles of the BIG and little 1

  1996cites this paper
• Interactions between Src Homology (SH) 2/SH3 Adapter Proteins and the Guanylnucleotide Exchange Factor SOS Are Differentially Regulated by Insulin and Epidermal Growth Factor*

  1996cites this paper
• Insulin stimulation of a MEK-dependent but ERK-independent SOS protein kinase

  1996cites this paper
• Structural aspects of signal transduction in B-cells.

  1996cites this paper
• Genetics of RAS Signaling in Drosophila

  1996cites this paper
• p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus.

  1996cites this paper
• Insulin-induced dissociation of Sos from Grb2 does not contribute to the down regulation of Ras activation.

  1996cites this paper
• G Protein-coupled Receptor Kinase GRK2 Is a Phospholipid-dependent Enzyme That Can Be Conditionally Activated by G Protein βγ Subunits*

  1996cites this paper
• Rho Is Required for Gαq and α1-Adrenergic Receptor Signaling in Cardiomyocytes

  1996cites this paper
• Isolated Sos1 PH Domain Exhibits Germinal Vesicle Breakdown-inducing Activity in Xenopus Oocytes*

  1996cites this paper
• Rho is required for Galphaq and alpha1-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathways.

  1996cites this paper
• Epidermal Growth Factor Receptor Targeting Prevents Uncoupling of the Grb2-SOS Complex (*)

  1996cites this paper
• Sos1 rapidly associates with Grb2 and is hypophosphorylated when complexed with the EGF receptor after EGF stimulation.

  1996cites this paper
• Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2

  1996cites this paper
• Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain.

  1995cites this paper
• Scratching the surface with the PH domain

  1995cites this paper