Skip to main content
SpringerLink
Log in

RasGRP Ras guanine nucleotide exchange factors in cancer

  • Review
  • Published:
Frontiers in Biology

Abstract

RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through -4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematologicalcancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanisms for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abel E L, Angel J M, Kiguchi K, DiGiovanni J (2009). Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applica- tions. Nat Protoc, 4(9): 1350–1362

    PubMed  CAS  Google Scholar 

  • Adachi R, Krilis S A, Nigrovic P A, Hamilton M J, Chung K, Thakurdas S M, Boyce J A, Anderson P, Stevens R L (2012). Ras guanine nucleotide-releasing protein-4 (RasGRP4) involvement in experimental arthritis and colitis. J Biol Chem, 287(24): 20047–20055

    PubMed  CAS  Google Scholar 

  • Ahearn I M, Haigis K, Bar-Sagi D, Philips M R (2012). Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol, 13(1): 39–51

    CAS  Google Scholar 

  • Ahuja H, Foti A, Bar-Eli M, Cline M (1990). The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing. Blood, 75: 1684–1690

    PubMed  CAS  Google Scholar 

  • Aiba Y, Oh-hora M, Kiyonaka S, Kimura Y, Hijikata A, Mori Y, Kurosaki T (2004). Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation. Proc Natl Acad Sci USA, 101(47): 16612–16617

    PubMed  CAS  Google Scholar 

  • Aifantis I, Raetz E, Buonamici S (2008). Molecular pathogenesis of Tcell leukaemia and lymphoma. Nat Rev Immunol, 8(5): 380–390

    PubMed  CAS  Google Scholar 

  • Alberola-Ila J, Hogquist K A, Swan K A, Bevan M J, Perlmutter R M (1996). Positive and negative selection invoke distinct signaling pathways. J Exp Med, 184(1): 9–18

    PubMed  CAS  Google Scholar 

  • Balgobind B V, Van Vlierberghe P, van den Ouweland A M W, Beverloo H B, Terlouw-Kromosoeto J N R, van Wering E R, Reinhardt D, Horstmann M, Kaspers G J L, Pieters R, Zwaan C M, Van den Heuvel-Eibrink M M, Meijerink J P (2008). Leukemiaassociated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood, 111(8): 4322–4328

    PubMed  CAS  Google Scholar 

  • Barata J T, Cardoso A A, Boussiotis V A (2005). Interleukin-7 in T-cell acute lymphoblastic leukemia: an extrinsic factor supporting leukemogenesis? Leuk Lymphoma, 46(4): 483–495

    PubMed  CAS  Google Scholar 

  • Barata J T, Keenan T D, Silva A, Nadler L M, Boussiotis V A, Cardoso A A (2004a). Common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia. Haematologica, 89(12): 1459–1467

    PubMed  CAS  Google Scholar 

  • Barata J T, Silva A, Brandao J G, Nadler L M, Cardoso A A, Boussiotis V A (2004b). Activation of PI3K is indispensable for interleukin 7- mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med, 200(5): 659–669

    PubMed  CAS  Google Scholar 

  • Beaulieu N, Zahedi B, Goulding R E, Tazmini G, Anthony K V, Omeis S L, de Jong D R, Kay R J (2007). Regulation of RasGRP1 by B cell antigen receptor requires cooperativity between three domains controlling translocation to the plasma membrane. Mol Biol Cell, 18(8): 3156–3168

    PubMed  CAS  Google Scholar 

  • Bell J J, Bhandoola A (2008). The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature, 452(7188): 764–767

    PubMed  CAS  Google Scholar 

  • Benschop R J, Cambier J C (1999). B cell development: signal transduction by antigen receptors and their surrogates. Curr Opin Immunol, 11(2): 143–151

    PubMed  CAS  Google Scholar 

  • Bergmeier W, Goerge T, Wang H W, Crittenden J R, Baldwin A C W, Cifuni S M, Housman D E, Graybiel A M, Wagner D D (2007). Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest, 117(6): 1699–1707

    PubMed  CAS  Google Scholar 

  • Berquam-Vrieze K E, Nannapaneni K, Brett B T, Holmfeldt L, Ma J, Zagorodna O, Jenkins N A, Copeland N G, Meyerholz D K, Knudson C M, Mullighan C G, Scheetz T E, Dupuy A J (2011). Cell of origin strongly influences genetic selection in a mouse model of T-ALL. Blood, 118(17): 4646–4656

    PubMed  CAS  Google Scholar 

  • Bivona T G, Pérez De Castro I, Ahearn I M, Grana T M, Chiu V K, Lockyer P J, Cullen P J, Pellicer A, Cox A D, Philips M R (2003). Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature, 424(6949): 694–698

    PubMed  CAS  Google Scholar 

  • Bos J L, Rehmann H, Wittinghofer A (2007). GEFs and GAPs: critical elements in the control of small G proteins. Cell, 129(5): 865–877

    PubMed  CAS  Google Scholar 

  • Botelho R J, Harrison R E, Stone J C, Hancock J F, Philips M R, Jongstra-Bilen J, Mason D, Plumb J, Gold M R, Grinstein S (2009). Localized diacylglycerol-dependent stimulation of Ras and Rap1 during phagocytosis. J Biol Chem, 284(42): 28522–28532

    PubMed  CAS  Google Scholar 

  • Boykevisch S, Zhao C, Sondermann H, Philippidou P, Halegoua S, Kuriyan J, Bar-Sagi D (2006). Regulation of ras signaling dynamics by Sos-mediated positive feedback. Curr Biol, 16(21): 2173–2179

    PubMed  CAS  Google Scholar 

  • Brodie C, Steinhart R, Kazimirsky G, Rubinfeld H, Hyman T, Ayres J N, Hur G M, Toth A, Yang D, Garfield S H, Stone J C, Blumberg P M (2004). PKCdelta associates with and is involved in the phosphorylation of RasGRP3 in response to phorbol esters. Mol Pharmacol, 66(1): 76–84

    PubMed  CAS  Google Scholar 

  • Cambier J C, Gauld S B, Merrell K T, Vilen B J (2007). B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nat Rev Immunol, 7(8): 633–643

    PubMed  CAS  Google Scholar 

  • Carbo C, Duerschmied D, Goerge T, Hattori H, Sakai J, Cifuni S M, White G C 2nd, Chrzanowska-Wodnicka M, Luo H R, Wagner D D (2010). Integrin-independent role of CalDAG-GEFI in neutrophil chemotaxis. J Leukoc Biol, 88(2): 313–319

    PubMed  CAS  Google Scholar 

  • Chakraborty A K, Roose J P (2013). Biochemical heterogeneity and developmental varieties in T-cell leukemia. Cell Cycle, 12(10): 1480–1481

    PubMed  CAS  Google Scholar 

  • Chan S M, Weng A P, Tibshirani R, Aster J C, Utz P J (2007). Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood, 110(1): 278–286

    PubMed  CAS  Google Scholar 

  • Chang L, Karin M (2001). Mammalian MAP kinase signalling cascades. Nature, 410(6824): 37–40

    PubMed  CAS  Google Scholar 

  • Chiarini F, Falà F, Tazzari P L, Ricci F, Astolfi A, Pession A, Pagliaro P, McCubrey J A, Martelli A M (2009). Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res, 69(8): 3520–3528

    PubMed  CAS  Google Scholar 

  • Chung J B, Silverman M, Monroe J G (2003). Transitional B cells: step by step towards immune competence. Trends Immunol, 24(6): 343–349

    PubMed  CAS  Google Scholar 

  • Cifuni S M, Wagner D D, Bergmeier W (2008). CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin alphaIIbbeta3 in platelets. Blood, 112(5): 1696–1703

    PubMed  CAS  Google Scholar 

  • Clyde-Smith J, Silins G, Gartside M, Grimmond S, Etheridge M, Apolloni A, Hayward N, Hancock J F (2000). Characterization of RasGRP2, a plasma membrane-targeted, dual specificity Ras/Rap exchange factor. J Biol Chem, 275(41): 32260–32267

    PubMed  CAS  Google Scholar 

  • Corey S J, Minden M D, Barber D L, Kantarjian H, Wang J C Y, Schimmer A D (2007). Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer, 7(2): 118–129

    PubMed  CAS  Google Scholar 

  • Coughlin J J, Stang S L, Dower N A, Stone J C (2005). RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. J Immunol (Baltimore, Md: 1950) 175(11): 7179–7184

    Google Scholar 

  • Coustan-Smith E, Mullighan C G, Onciu M, Behm F G, Raimondi S C, Pei D, Cheng C, Su X, Rubnitz J E, Basso G, Biondi A, Pui C H, Downing J R, Campana D (2009). Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol, 10(2): 147–156

    PubMed  CAS  Google Scholar 

  • Crittenden J R, Bergmeier W, Zhang Y, Piffath C L, Liang Y, Wagner D D, Housman D E, Graybiel A M (2004). CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med, 10(9): 982–986

    PubMed  CAS  Google Scholar 

  • Dail M, Li Q, McDaniel A, Wong J, Akagi K, Huang B, Kang H C, Kogan S C, Shokat K, Wolff L, Braun B S, Shannon K (2010). Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents. Proc Natl Acad Sci USA, 107(11): 5106–5111

    PubMed  CAS  Google Scholar 

  • Dal Porto J M, Gauld S B, Merrell K T, Mills D, Pugh-Bernard A E, Cambier J (2004). B cell antigen receptor signaling 101. Mol Immunol, 41(6–7): 599–613

    Google Scholar 

  • Daniels M A, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, Werlen G, Holländer G A, Gascoigne N R J, Palmer E (2006). Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature, 444(7120): 724–729

    PubMed  CAS  Google Scholar 

  • Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty A K, Roose J P (2009). Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell, 136(2): 337–351

    PubMed  CAS  Google Scholar 

  • de la Luz Sierra M, Sakakibara S, Gasperini P, Salvucci O, Jiang K, McCormick P J, Segarra M, Stone J, Maric D, Zhu J, Qian X, Lowy D R, Tosato G (2010). The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1. Blood, 115(19): 3970–3979

    PubMed  Google Scholar 

  • DeAngelo D J (2006). A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia (T-ALL) and other leukemias. J Clin Oncol, 24(18 Suppl): 6585

    Google Scholar 

  • DeFranco A L (2000). B-cell activation 2000. Immunol Rev, 176: 5–9

    PubMed  CAS  Google Scholar 

  • Diaz-Flores E, Hana Goldschmidt, Philippe Depeille, Victor Ng, Kimberly Krisman, Michael Crone, Michael R. Burgess, Olusegun Williams, Benjamin Houseman, Kevan Shokat, et al. (2013). PLCγ and PI3 kinase link cytokine stimulation to ERK activation in primary hematopoietic cells expressing normal and oncogenic Kras. Science Signaling, (In press)

    Google Scholar 

  • Diehn M, Alizadeh A A, Rando O J, Liu C L, Stankunas K, Botstein D, Crabtree G R, Brown P O (2002). Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci USA, 99(18): 11796–11801

    PubMed  CAS  Google Scholar 

  • Diez F R, Garrido A A, Sharma A, Luke C T, Stone J C, Dower N A, Cline J M, Lorenzo P S (2009). RasGRP1 transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factor. Am J Pathol, 175(1): 392–399

    PubMed  CAS  Google Scholar 

  • Dower N A, Stang S L, Bottorff D A, Ebinu J O, Dickie P, Ostergaard H L, Stone J C (2000). RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat Immunol, 1(4): 317–321

    PubMed  CAS  Google Scholar 

  • Dührsen U, Stahl J, Gough NM (1990). In vivo transformation of factordependent hemopoietic cells: role of intracisternal A-particle transposition for growth factor gene activation. EMBO J, 9(4): 1087–1096

    PubMed  Google Scholar 

  • Ebinu J O, Bottorff D A, Chan E Y, Stang S L, Dunn R J, Stone J C (1998). RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science, 280(5366): 1082–1086

    PubMed  CAS  Google Scholar 

  • Ebinu J O, Stang S L, Teixeira C, Bottorff D A, Hooton J, Blumberg P M, Barry M, Bleakley R C, Ostergaard H L, Stone J C (2000). RasGRP links T-cell receptor signaling to Ras. Blood, 95(10): 3199–3203

    PubMed  CAS  Google Scholar 

  • Emanuel P D, Bates L J, Castleberry R P, Gualtieri R J, Zuckerman K S (1991). Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood, 77(5): 925–929

    PubMed  CAS  Google Scholar 

  • Feldman B J, Feldman D (2001). The development of androgen-independent prostate cancer. Nat Rev Cancer, 1(1): 34–45

    PubMed  CAS  Google Scholar 

  • Ferrando A A, Neuberg D S, Staunton J, Loh M L, Huard C, Raimondi S C, Behm F G, Pui C H, Downing J R, Gilliland D G, Lander E S, Golub T R, Look A T (2002). Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell, 1(1): 75–87

    PubMed  CAS  Google Scholar 

  • Feske S (2007). Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol, 7(9): 690–702

    PubMed  CAS  Google Scholar 

  • Friday B B, Adjei A A (2005). K-ras as a target for cancer therapy. Biochimica et Biophysica Acta (BBA) — Rev Can, 1756: 127–144

    CAS  Google Scholar 

  • Fuller D M, Zhu M, Song X, Ou-Yang C W, Sullivan S A, Stone J C, Zhang W (2012). Regulation of RasGRP1 function in T cell development and activation by its unique tail domain. PLoS ONE, 7(6): e38796

    PubMed  CAS  Google Scholar 

  • Ghandour H, Cullere X, Alvarez A, Luscinskas F W, Mayadas T N (2007). Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion. Blood, 110(10): 3682–3690

    PubMed  CAS  Google Scholar 

  • Gifford J L, Walsh M P, Vogel H J (2007). Structures and metal-ionbinding properties of the Ca2+-binding helix-loop-helix EF-hand motifs. Biochem J, 405(2): 199–221

    PubMed  CAS  Google Scholar 

  • Golec D P, Dower N A, Stone J C, Baldwin T A (2013). RasGRP1, but not RasGRP3, is required for efficient thymic β-selection and ERK activation downstream of CXCR4. PLoS ONE, 8(1): e53300

    PubMed  CAS  Google Scholar 

  • Goodnow C C, Crosbie J, Jorgensen H, Brink R A, Basten A (1989). Induction of self-tolerance in mature peripheral B lymphocytes. Nature, 342(6248): 385–391

    PubMed  CAS  Google Scholar 

  • Grabarek Z (2006). Structural basis for diversity of the EF-hand calciumbinding proteins. J Mol Biol, 359(3): 509–525

    PubMed  CAS  Google Scholar 

  • Grabher C, von Boehmer H, Look A T (2006). Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer, 6(5): 347–359

    PubMed  CAS  Google Scholar 

  • Graux C, Cools J, Michaux L, Vandenberghe P, Hagemeijer A (2006). Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia, 20(9): 1496–1510

    PubMed  CAS  Google Scholar 

  • Grisendi S, Mecucci C, Falini B, Pandolfi P P (2006). Nucleophosmin and cancer. Nat Rev Cancer, 6(7): 493–505

    PubMed  CAS  Google Scholar 

  • Guilbault B, Kay R J (2004). RasGRP1 sensitizes an immature B cell line to antigen receptor-induced apoptosis. J Biol Chem, 279(19): 19523–19530

    PubMed  CAS  Google Scholar 

  • Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, Dahlberg S, Neuberg D, Moreau L A, Winter S S, Larson R, Zhang J, Protopopov A, Chin L, Pandolfi P P, Silverman L B, Hunger S P, Sallan S E, Look A T (2009). High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood, 114(3): 647–650

    PubMed  CAS  Google Scholar 

  • Hartzell C, Ksionda O, Lemmens E, Coakley K, Yang M, Dail M, Harvey R C, Govern C, Bakker J, Lenstra T L, Ammon K, Boeter A, Winter S S, Loh M, Shannon K, Chakraborty A K, Wabl M, Roose J P (2013). Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis. Sci Signal, 6(268): ra21

    PubMed  CAS  Google Scholar 

  • Hertz M, Nemazee D (1997). BCR ligation induces receptor editing in IgM+IgD— bone marrow B cells in vitro. Immunity, 6(4): 429–436

    PubMed  CAS  Google Scholar 

  • Izquierdo M, Downward J, Graves J D, Cantrell D A (1992). Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells. Mol Cell Biol, 12(7): 3305–3312

    PubMed  CAS  Google Scholar 

  • Janas ML, Turner M (2011). Interaction of Ras with P110 is required for thymic-selection in the mouse. J Immunol (Baltimore, Md: 1950) 187: 4667–4675

    Google Scholar 

  • Johnson J E, Goulding R E, Ding Z, Partovi A, Anthony K V, Beaulieu N, Tazmini G, Cornell R B, Kay R J (2007). Differential membrane binding and diacylglycerol recognition by C1 domains of RasGRPs. Biochem J, 406(2): 223–236

    PubMed  CAS  Google Scholar 

  • Jun J E, Ignacio Rubio, Roose J P (2013). Regulation of Ras exchange factors and cellular localization of Ras activation by lipid messengers in T cells. Fronit Immunol, (In press) doi: 10.3389/fimmu.2013.00239

    Google Scholar 

  • Kawamura M, Ohnishi H, Guo S X, Sheng X M, Minegishi M, Hanada R, Horibe K, Hongo T, Kaneko Y, Bessho F, Yanagisawa M, Sekiya T, Hayashi Y (1999). Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia. Leuk Res, 23(2): 115–126

    PubMed  CAS  Google Scholar 

  • Kawasaki H, Springett GM, Toki S, Canales J J, Harlan P, Blumenstiel J P, Chen E J, Bany I A, Mochizuki N, Ashbacher A, Matsuda M, Housman D E, Graybiel A M (1998). A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. Proc Natl Acad Sci USA, 95(22): 13278–13283

    PubMed  CAS  Google Scholar 

  • Khandanpour C, Phelan J D, Vassen L, Schütte J, Chen R, Horman S R, Gaudreau M C, Krongold J, Zhu J, Paul W E, Dührsen U, Göttgens B, Grimes H L, Möröy T (2013). Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell, 23(2): 200–214

    PubMed  CAS  Google Scholar 

  • Kim R, Trubetskoy A, Suzuki T, Jenkins N A, Copeland N G, Lenz J (2003). Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphomas. J Virol, 77(3): 2056–2062

    PubMed  CAS  Google Scholar 

  • Klein L, Hinterberger M, Wirnsberger G, Kyewski B (2009). Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol, 9(12): 833–844

    PubMed  CAS  Google Scholar 

  • Klinger M B, Guilbault B, Goulding R E, Kay R J (2005). Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors. Oncogene, 24(16): 2695–2704

    PubMed  CAS  Google Scholar 

  • Knudsen B S, Edlund M (2004). Prostate cancer and the met hepatocyte growth factor receptor. Adv Cancer Res, 91: 31–67

    PubMed  CAS  Google Scholar 

  • Koike K, Matsuda K (2008). Recent advances in the pathogenesis and management of juvenile myelomonocytic leukaemia. Br J Haematol, 141(5): 567–575

    PubMed  CAS  Google Scholar 

  • Kortum R L, Rouquette-Jazdanian A K, Samelson L E (2013). Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells. Trends Immunol, 34(6): 1–10

    Google Scholar 

  • Kortum R L, Sommers C L, Alexander C P, Pinski J M, Li W, Grinberg A, Lee J, Love P E, Samelson L E (2011). Targeted Sos1 deletion reveals its critical role in early T-cell development. Proc Natl Acad Sci USA, 108(30): 12407–12412

    PubMed  CAS  Google Scholar 

  • Kortum R L, Sommers C L, Pinski J M, Alexander C P, Merrill R K, Li W, Love P E, Samelson L E (2012). Deconstructing Ras signaling in the thymus. Mol Cell Biol, 32(14): 2748–2759

    PubMed  CAS  Google Scholar 

  • Kremer K N, Kumar A, Hedin K E (2011). G i2 and ZAP-70 mediate RasGRP1 membrane localization and activation of SDF-1-induced T cell functions. J Immunol (Baltimore, Md: 1950), 187: 3177–3185

    Google Scholar 

  • Kurosaki T (1999). Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol, 17(1): 555–592

    PubMed  CAS  Google Scholar 

  • Lam K P, Kühn R, Rajewsky K (1997). In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell, 90(6): 1073–1083

    PubMed  CAS  Google Scholar 

  • Lauchle J O, Kim D, Le D T, Akagi K, Crone M, Krisman K, Warner K, Bonifas J M, Li Q, Coakley K M, Diaz-Flores E, Gorman M, Przybranowski S, Tran M, Kogan S C, Roose J P, Copeland N G, Jenkins N A, Parada L, Wolff L, Sebolt-Leopold J, Shannon K (2009). Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature, 461(7262): 411–414

    PubMed  CAS  Google Scholar 

  • Lee J R, Koretzky G A (1998). Extracellular signal-regulated kinase-2, but not c-Jun NH2-terminal kinase, activation correlates with surface IgM-mediated apoptosis in the WEHI 231 B cell line. J Immunol, 161(4): 1637–1644

    PubMed  CAS  Google Scholar 

  • Lee M J, Ye A S, Gardino A K, Heijink A M, Sorger P K, MacBeath G, Yaffe M B (2012). Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell, 149(4): 780–794

    PubMed  CAS  Google Scholar 

  • Lee S H, Yun S, Lee J, Kim MJ, Piao Z-H, Jeong M, Chung JW, Kim TD, Yoon S R, Greenberg P D, Choi I (2009). RasGRP1 is required for human NK cell function. J Immunol (Baltimore, Md: 1950) 183: 7931–7938

    Google Scholar 

  • Li L, Yang Y, Wong G W, Stevens R L (2003). Mast cells in airway hyporesponsive C3H/HeJ mice express a unique isoform of the signaling protein Ras guanine nucleotide releasing protein 4 that is unresponsive to diacylglycerol and phorbol esters. J Immunol (Baltimore, Md: 1950), 171: 390–397

    Google Scholar 

  • Limnander A, Depeille P, Freedman T S, Liou J, Leitges M, Kurosaki T, Roose J P, Weiss A (2011). STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nat Immunol, 12(5): 425–433

    PubMed  CAS  Google Scholar 

  • Limnander A, Weiss A (2011). Ca-dependent Ras/Erk signaling mediates negative selection of autoreactive B cells. Small GTPases, 2(5): 282–288

    PubMed  Google Scholar 

  • Lorenzo P S, Beheshti M, Pettit G R, Stone J C, Blumberg P M (2000). The guanine nucleotide exchange factor RasGRP is a high-affinity target for diacylglycerol and phorbol esters. Mol Pharmacol, 57(5): 840–846

    PubMed  CAS  Google Scholar 

  • Lorenzo P S, Kung JW, Bottorff D A, Garfield S H, Stone J C, Blumberg P M (2001). Phorbol esters modulate the Ras exchange factor RasGRP3. Cancer Res, 61(3): 943–949

    PubMed  CAS  Google Scholar 

  • Luke C T, Oki-Idouchi C E, Cline J M, Lorenzo P S (2007). RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesis. Cancer Res, 67(21): 10190–10197

    PubMed  CAS  Google Scholar 

  • Maser R S, Choudhury B, Campbell P J, Feng B, Wong K K, Protopopov A, O’Neil J, Gutierrez A, Ivanova E, Perna I, Lin E, Mani V, Jiang S, McNamara K, Zaghlul S, Edkins S, Stevens C, Brennan C, Martin E S, Wiedemeyer R, Kabbarah O, Nogueira C, Histen G, Aster J, Mansour M, Duke V, Foroni L, Fielding A K, Goldstone A H, Rowe J M, Wang Y A, Look A T, Stratton M R, Chin L, Futreal P A, DePinho R A (2007). Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature, 447(7147): 966–971

    PubMed  CAS  Google Scholar 

  • Melamed D, Benschop R J, Cambier J C, Nemazee D (1998). Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell, 92(2): 173–182

    PubMed  CAS  Google Scholar 

  • Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E, Berns A, Romeyn L (2002). High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet, 32(1): 153–159

    PubMed  CAS  Google Scholar 

  • Mor A, Philips M R (2006). Compartmentalized Ras/MAPK signaling. Annu Rev Immunol, 24(1): 771–800

    PubMed  CAS  Google Scholar 

  • Navarro M N, Goebel J, Feijoo-Carnero C, Morrice N, Cantrell D A (2011). Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat Immunol, 12(4): 352–361

    PubMed  CAS  Google Scholar 

  • Norment AM, Bogatzki L Y, Klinger M, Ojala EW, Bevan MJ, Kay R J (2003). Transgenic expression of RasGRP1 induces the maturation of double-negative thymocytes and enhances the production of CD8 single-positive thymocytes. J Immunol (Baltimore, Md: 1950), 170: 1141–1149

    Google Scholar 

  • Oh-hora M, Johmura S, Hashimoto A, Hikida M, Kurosaki T (2003). Requirement for Ras guanine nucleotide releasing protein 3 in coupling phospholipase C-gamma2 to Ras in B cell receptor signaling. J Exp Med, 198(12): 1841–1851

    PubMed  CAS  Google Scholar 

  • Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T, Harada H, Kitamura T (2011). Aberrant expression of RasGRP1 cooperates with gain-offunction NOTCH1 mutations in T-cell leukemogenesis. Leukemia

    Google Scholar 

  • Oki-Idouchi C E, Lorenzo P S (2007). Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin. Cancer Res, 67(1): 276–280

    PubMed  CAS  Google Scholar 

  • Palomero T, Barnes K C, Real P J, Glade Bender J L, Sulis M L, Murty V V, Colovai A I, Balbin M, Ferrando A A (2006a). CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gammasecretase inhibitors. Leukemia, 20(7): 1279–1287

    PubMed  CAS  Google Scholar 

  • Palomero T, Lim W K, Odom D T, Sulis M L, Real P J, Margolin A, Barnes K C, O’Neil J, Neuberg D, Weng A P, Aster J C, Sigaux F, Soulier J, Look A T, Young R A, Califano A, Ferrando AA (2006b). NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Nat Acad Sci U S A, 103(48): 18261–18266

    CAS  Google Scholar 

  • Palomero T, Sulis M L, Cortina M, Real P J, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins S L, Bhagat G, Agarwal A M, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zúñiga-Pflücker J C, Dominguez M, Ferrando A A (2007). Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med, 13(10): 1203–1210

    PubMed  CAS  Google Scholar 

  • Pawson T, Linding R (2008). Network medicine. FEBS Lett, 582(8): 1266–1270

    PubMed  CAS  Google Scholar 

  • Perez-Losada J, Balmain A (2003). Stem-cell hierarchy in skin cancer. Nat Rev Cancer, 3(6): 434–443

    PubMed  CAS  Google Scholar 

  • Pieters R, Carroll W L, (2008). Biology and treatment of acute lymphoblastic leukemia. Pediatric Clinics of NA 24: 1–20

    Google Scholar 

  • Pillai S (1999). The chosen few? Positive selection and the generation of naive B lymphocytes. Immunity, 10(5): 493–502

    PubMed  CAS  Google Scholar 

  • Pillai S, Cariappa A (2009). The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol, 9(11): 767–777

    PubMed  CAS  Google Scholar 

  • Pillai S, Cariappa A, Moran S T (2004). Positive selection and lineage commitment during peripheral B-lymphocyte development. Immunol Rev, 197(1): 206–218

    PubMed  CAS  Google Scholar 

  • Priatel J J, Teh S J, Dower N A, Stone J C, Teh H S (2002). RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation. Immunity, 17(5): 617–627

    PubMed  CAS  Google Scholar 

  • Rajalingam K, Schreck R, Rapp U R, Albert S (2007). Ras oncogenes and their downstream targets. Biochim Biophys Acta, 1773(8): 1177–1195

    PubMed  CAS  Google Scholar 

  • Rambaratsingh R A, Stone J C, Blumberg P M, Lorenzo P S (2003). RasGRP1 represents a novel non-protein kinase C phorbol ester signaling pathway in mouse epidermal keratinocytes. J Biol Chem, 278(52): 52792–52801

    PubMed  CAS  Google Scholar 

  • Ratushny V, Gober M D, Hick R, Ridky TW, Seykora J T (2012). From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J Clin Invest, 122(2): 464–472

    PubMed  CAS  Google Scholar 

  • Reuther G W, Lambert Q T, Rebhun J F, Caligiuri M A, Quilliam L A, Der C J (2002). RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. J Biol Chem, 277(34): 30508–30514

    PubMed  CAS  Google Scholar 

  • Roberts D M, Anderson A L, Hidaka M, Swetenburg R L, Patterson C, Stanford W L, Bautch V L (2004). A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Mol Cell Biol, 24(24): 10515–10528

    PubMed  CAS  Google Scholar 

  • Rogers S Y, Bradbury D, Kozlowski R, Russell N H (1994). Evidence for internal autocrine regulation of growth in acute myeloblastic leukemia cells. Exp Hematol, 22(7): 593–598

    PubMed  CAS  Google Scholar 

  • Roose J P, Mollenauer M, Gupta V A, Stone J, Weiss A (2005). A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells. Mol Cell Biol, 25(11): 4426–4441

    PubMed  CAS  Google Scholar 

  • Roose J P, Mollenauer M, Ho M, Kurosaki T, Weiss A (2007). Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Mol Cell Biol, 27(7): 2732–2745

    PubMed  CAS  Google Scholar 

  • Ruiz S, Santos E, Bustelo X R (2007). RasGRF2, a guanosine nucleotide exchange factor for Ras GTPases, participates in T-cell signaling responses. Mol Cell Biol, 27(23): 8127–8142

    PubMed  CAS  Google Scholar 

  • Sharma A, Luke C T, Dower N A, Stone J C, Lorenzo P S (2010). RasGRP1 is essential for ras activation by the tumor promoter 12-Otetradecanoylphorbol- 13-acetate in epidermal keratinocytes. J Biol Chem, 285(21): 15724–15730

    PubMed  CAS  Google Scholar 

  • Silva A, Laranjeira A B A, Martins L R, Cardoso B A, Demengeot J, Yunes J A, Seddon B, Barata J T (2011). IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. Cancer Res, 71(14): 4780–4789

    PubMed  CAS  Google Scholar 

  • Smith-Garvin J E, Koretzky G A, Jordan M S (2009). T cell activation. Annu Rev Immunol, 27(1): 591–619

    PubMed  CAS  Google Scholar 

  • Stang S L, Lopez-Campistrous A, Song X, Dower N A, Blumberg P M, Wender P A, Stone J C (2009). A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells. Exp Hematol, 37(1): 122–134, 134.e2

    PubMed  CAS  Google Scholar 

  • Starr T K, Jameson S C, Hogquist K A (2003). Positive and negative selection of T cells. Annu Rev Immunol, 21(1): 139–176

    PubMed  CAS  Google Scholar 

  • Stolla M, Stefanini L, André P, Ouellette T D, Reilly M P, McKenzie S E, Bergmeier W (2011). CalDAG-GEFI deficiency protects mice in a novel model of Fcγ RIIA-mediated thrombosis and thrombocytopenia. Blood, 118(4): 1113–1120

    PubMed  CAS  Google Scholar 

  • Stone J C (2011). Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells. Genes & Cancer, 2: 320–334

    CAS  Google Scholar 

  • Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian Z R, Du J, Davis A, Mongare M M, Gould J, Frederick D T, Cooper Z A, Chapman P B, Solit D B, Ribas A, Lo R S, Flaherty K T, Ogino S, Wargo J A, Golub T R (2012). Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature, 487(7408): 500–504

    PubMed  CAS  Google Scholar 

  • Su T T, Guo B, Wei B, Braun J, Rawlings D J (2004). Signaling in transitional type 2 B cells is critical for peripheral B-cell development. Immunol Rev, 197(1): 161–178

    PubMed  CAS  Google Scholar 

  • Subramaniam P S, Whye D W, Efimenko E, Chen J, Tosello V, De Keersmaecker K, Kashishian A, Thompson M A, Castillo M, Cordon-Cardo C, Davé U P, Ferrando A, Lannutti B J, Diacovo T G (2012). Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell, 21(4): 459–472

    PubMed  CAS  Google Scholar 

  • Suire S, Lécureuil C, Anderson K E, Damoulakis G, Niewczas I, Davidson K, Guillou H, Pan D, Clark J, Hawkins P T, Stephens L (2012). GPCR activation of Ras and PI3Kγ in neutrophils depends on PLCβ2/β3 and the RasGEF RasGRP4. EMBO J, 31(14): 3118–3129

    PubMed  CAS  Google Scholar 

  • Suzuki T, Shen H, Akagi K, Morse H C, Malley J D, Naiman D Q, Jenkins N A, Copeland N G (2002). New genes involved in cancer identified by retroviral tagging. Nat Genet, 32(1): 166–174

    PubMed  CAS  Google Scholar 

  • Tazmini G, Beaulieu N, Woo A, Zahedi B, Goulding R E, Kay R J (2009). Membrane localization of RasGRP1 is controlled by an EFhand, and by the GEF domain. Biochim Biophys Acta, 1793(3): 447–461

    PubMed  CAS  Google Scholar 

  • Teixeira C, Stang S L, Zheng Y, Beswick N S, Stone J C (2003). Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3. Blood, 102(4): 1414–1420

    PubMed  CAS  Google Scholar 

  • Torres R M, Flaswinkel H, Reth M, Rajewsky K (1996). Aberrant B cell development and immune response in mice with a compromised BCR complex. Science, 272(5269): 1804–1808

    PubMed  CAS  Google Scholar 

  • Townsend S E, Weintraub B C, Goodnow C C (1999). Growing up on the streets: why B-cell development differs from T-cell development. Immunol Today, 20(5): 217–220

    PubMed  CAS  Google Scholar 

  • Vassiliou G S, Cooper J L, Rad R, Li J, Rice S, Uren A, Rad L, Ellis P, Andrews R, Banerjee R, Grove C, Wang W, Liu P, Wright P, Arends M, Bradley A (2011). Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice. Nat Genet, 43(5): 470–475

    PubMed  CAS  Google Scholar 

  • Vetter I R, Wittinghofer A (2001). The guanine nucleotide-binding switch in three dimensions. Science, 294(5545): 1299–1304

    PubMed  CAS  Google Scholar 

  • Vigil D, Cherfils J, Rossman K L, Der C J (2010). Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer, 10(12): 842–857

    PubMed  CAS  Google Scholar 

  • Vogelstein B, Papadopoulos N, Velculescu V E, Zhou S, Diaz L A Jr, Kinzler K W (2013). Cancer genome landscapes. Science, 339(6127): 1546–1558

    PubMed  CAS  Google Scholar 

  • von Lintig F C, Huvar I, Law P, Diccianni M B, Yu A L, Boss G R (2000). Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia. Clin Cancer Res, 6(5): 1804–1810

    Google Scholar 

  • Wada H, Masuda K, Satoh R, Kakugawa K, Ikawa T, Katsura Y, Kawamoto H (2008). Adult T-cell progenitors retain myeloid potential. Nature, 452(7188): 768–772

    PubMed  CAS  Google Scholar 

  • Ward A F, Braun B S, Shannon K M (2012). Targeting oncogenic Ras signaling in hematologic malignancies. Blood, 120(17): 3397–3406

    PubMed  CAS  Google Scholar 

  • Watanabe-Okochi N, Oki T, Komeno Y, Kato N, Yuji K, Ono R, Harada Y, Harada H, Hayashi Y, Nakajima H, Nosaka T, Kitaura J, Kitamura T (2009). Possible involvement of RasGRP4 in leukemogenesis. Int J Hematol, 89(4): 470–481

    PubMed  CAS  Google Scholar 

  • Weng A P, Ferrando A A, Lee W, Morris J P 4th, Silverman L B, Sanchez-Irizarry C, Blacklow S C, Look A T, Aster J C (2004). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 306(5694): 269–271

    PubMed  CAS  Google Scholar 

  • Weng A P, Millholland J M, Yashiro-Ohtani Y, Arcangeli M L, Lau A, Wai C, Del Bianco C, Rodriguez C G, Sai H, Tobias J, Li Y, Wolfe M S, Shachaf C, Felsher D, Blacklow S C, Pear W S, et al Aster J C (2006). c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes & Dev, 20: 2096–2109

    CAS  Google Scholar 

  • Wilson T R, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin D P, Koeppen H, Merchant M, Neve R, Settleman J (2012). Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature, 487(7408): 505–509

    PubMed  CAS  Google Scholar 

  • Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (2001). Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood, 97(8): 2434–2439

    PubMed  CAS  Google Scholar 

  • Yamashita S, Mochizuki N, Ohba Y, Tobiume M, Okada Y, Sawa H, Nagashima K, Matsuda M (2000). CalDAG-GEFIII activation of Ras, R-ras, and Rap1. J Biol Chem, 275(33): 25488–25493

    PubMed  CAS  Google Scholar 

  • Yang D, Kedei N, Li L, Tao J, Velasquez J F, Michalowski A M, Tóth B I, Marincsák R, Varga A, Bíró T, Yuspa S H, Blumberg P M (2010). RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. Cancer Res, 70(20): 7905–7917

    PubMed  CAS  Google Scholar 

  • Yang D, Tao J, Li L, Kedei N, Tóth Z E, Czap A, Velasquez J F, Mihova D, Michalowski A M, Yuspa S H, Blumberg P M (2011). RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma. 30: 4590–460

    CAS  Google Scholar 

  • Yang Y, Li L, Wong G W, Krilis S A, Madhusudhan M S, Sali A, Stevens R L (2002). RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol- binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function. J Biol Chem, 277(28): 25756–25774

    PubMed  CAS  Google Scholar 

  • Yasuda T, Kometani K, Takahashi N, Imai Y, Aiba Y, Kurosaki T (2011). ERKs induce expression of the transcriptional repressor Blimp-1 and subsequent plasma cell differentiation. Sci Signal, 4(169): ra25

    PubMed  Google Scholar 

  • Yasuda T, Kurosaki T (2008). Regulation of lymphocyte fate by Ras/ ERK signals. Cell Cycle, 7(23): 3634–3640

    PubMed  CAS  Google Scholar 

  • Yasuda T, Sanjo H, Pagès G, Kawano Y, Karasuyama H, Pouysségur J, Ogata M, Kurosaki T (2008). Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity, 28(4): 499–508

    PubMed  CAS  Google Scholar 

  • Yokota S, Nakao M, Horiike S, Seriu T, Iwai T, Kaneko H, Azuma H, Oka T, Takeda T, Watanabe A, Kikuta A, Asami K, Sekine I, Matsushita T, Tsuhciya T, Mimaya J, Koizumi S, Miyake M, Nishikawa K, Takaue Y, Kawano Y, Iwai A, Ishida Y, Matsumoto K, Fujimoto T (1998). Mutational analysis of the N-ras gene in acute lymphoblastic leukemia: a study of 125 Japanese pediatric cases. Int J Hematol, 67(4): 379–387

    PubMed  CAS  Google Scholar 

  • Young D C, Griffin J D (1986). Autocrine secretion of GM-CSF in acute myeloblastic leukemia. Blood, 68(5): 1178–1181

    PubMed  CAS  Google Scholar 

  • Zahedi B, Goo H J, Beaulieu N, Tazmini G, Kay R J, Cornell R B (2011). Phosphoinositide 3-kinase regulates plasma membrane targeting of the Ras-specific exchange factor RasGRP1. J Biol Chem, 286(14): 12712–12723

    PubMed  CAS  Google Scholar 

  • Zenatti P P, Ribeiro D, Li W, Zuurbier L, Silva M C, Paganin M, Tritapoe J, Hixon J A, Silveira A B, Cardoso B A, Sarmento L M, Correia N, Toribio M L, Kobarg J, Horstmann M, Pieters R, Brandalise S R, Ferrando A A, Meijerink J P, Durum S K, Yunes J A, Barata J T (2011). Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet, 43(10): 932–939

    PubMed  CAS  Google Scholar 

  • Zhang J, Ding L, Holmfeldt L, Wu G, Heatley S L, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen S C, Wei L, Collins-Underwood J R, Ma J, Roberts K G, Pounds S B, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki R W, Parker M, McGoldrick D J, Zhao D, Alford D, Espy S, Bobba K C, Song G, Pei D, Cheng C, Roberts S, Barbato M I, Campana D, Coustan-Smith E, Shurtleff S A, Raimondi S C, Kleppe M, Cools J, Shimano K A, Hermiston M L, Doulatov S, Eppert K, Laurenti E, Notta F, Dick J E, Basso G, Hunger S P, Loh M L, Devidas M, Wood B, Winter S, Dunsmore K P, Fulton R S, Fulton L L, Hong X, Harris C C, Dooling D J, Ochoa K, Johnson K J, Obenauer J C, Evans W E, Pui C H, Naeve C W, Ley T J, Mardis E R, Wilson R K, Downing J R, Mullighan C G (2012). The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature, 481(7380): 157–163

    PubMed  CAS  Google Scholar 

  • Zheng Y, Liu H, Coughlin J, Zheng J, Li L, Stone J C (2005). Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells. Blood, 105(9): 3648–3654

    PubMed  CAS  Google Scholar 

  • Zhu M, Fuller DM, Zhang W (2012). The role of Ras guanine nucleotide releasing protein 4 in Fc epsilonRI-mediated signaling, mast cell function, and T cell development. J Biol Chem, 287(11): 8135–8143

    PubMed  CAS  Google Scholar 

  • Zikherman J, Parameswaran R, Weiss A (2012). Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature, 489(7414): 160–164

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy, University of California, San Francisco, San Francisco, CA, 94143, USA

    Olga Ksionda, Andre Limnander & Jeroen P. Roose

Authors
  1. Olga Ksionda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andre Limnander
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeroen P. Roose
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeroen P. Roose.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ksionda, O., Limnander, A. & Roose, J.P. RasGRP Ras guanine nucleotide exchange factors in cancer. Front. Biol. 8, 508–532 (2013). https://doi.org/10.1007/s11515-013-1276-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-013-1276-9

Keywords

Search

Navigation