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Front Biol    2013, Vol. 8 Issue (5) : 508-532    https://doi.org/10.1007/s11515-013-1276-9
REVIEW
RasGRP Ras guanine nucleotide exchange factors in cancer
Olga KSIONDA, Andre LIMNANDER, Jeroen P. ROOSE()
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
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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 hematological-cancers 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.
Keywords Ras      signaling      lymphocytes      cancer      RasGRP      receptor     
Corresponding Author(s): ROOSE Jeroen P.,Email:jeroen.roose@ucsf.edu   
Issue Date: 01 October 2013
 Cite this article:   
Olga KSIONDA,Andre LIMNANDER,Jeroen P. ROOSE. RasGRP Ras guanine nucleotide exchange factors in cancer[J]. Front Biol, 2013, 8(5): 508-532.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-013-1276-9
https://academic.hep.com.cn/fib/EN/Y2013/V8/I5/508
Fig.1  Domain structure of RasGRP proteins. REM (Ras exchange motif) and Cdc25 domain form the catalytic core and catalyze GDP to GTP exchange on Ras and Rap GTPases. Two EF hands bind calcium ions and may be important for proper localization and/or GEF regulation. C1 domain of all family members but RasGRP2 binds diacylglycerol and that is crucial for anchoring at the plasma membrane. Finally, RasGRP1 uniquely possess C-terminal tail whose function is unknown but is likely to mediate protein–protein interactions. Conserved phosphorylation sites thought to be important for RasGRPs activation are indicated. All illustrations in this review were made by Anna Hupalowska.
Fig.2  Activation of RasGRP1/3 downstream of TCR/BCR receptor.
(A) Overview of TCR-induced RasGRP1-Ras-MAPK cascade. Recognition of the cognate peptide by TCR results in the activation of tyrosine kinase ZAP70, which phosphorylates multiple downstream targets. One of them, the adaptor protein LAT participates in the assembly of a signaling complex containing PLCγ1. PLCγ1 hydrolyses PIP2 present in the plasma membrane into IP and DAG. IP is essential for the release of calcium from internal stores, whereas DAG activates RasGRP1, a GEF for Ras GTPase and initiates MAPK cascade. Note that the composition of the TCR chains and the proximal TCR signaling event are simplified here for clarity.
(B) Overview of BCR-induced RasGRP3-Ras-MAPK cascade.Antigen engagement on the BCR leads to activation of the tyrosine kinase Syk. Activated Syk phosphorylates multiple downstream targets, including the adaptor BLNK/SLP-65, which nucleates a signaling complex containing PLCγ2. This leads to hydrolysis of PIP2 into IP3 and DAG. IP3 binds the IP3 receptor on the ER, leading to release of intracellular calcium stores and store-operated calcium entry, while DAG recruits RasGRP1 and RasGRP3 to the plasma membrane and initiates MAPK signaling.
Fig.3  Overview of T cell development and the role of RasGRPs. The expression of CD4 and CD8 marks different stages of T cell development. Early progenitors do not express CD4 or CD8 and are termed double negative (DN). Depending on the expression of other markers those cells are further subdivided into 4 different subsets (DN1–4). DN3 thymocytes express an immature form of the TCR, pre-TCR. Signals from this receptor results in survival, burst of proliferation and differentiation into double positive cells, which express both CD4 and CD8. This process is called β-selection process. Subsequently, signaling from the TCR leads to positive and negative selection, a process depending on avidity of binding to self-peptide-MHC complexes presented by stromal cells in the thymus. Cells differentiate into single positive CD4 or CD8 thymocytes. These cells leave the thymus and migrate to secondary lymphoid organs. RasGRP1 is important for both signaling downstream of pre-TCR as well as for the negative and positive selection. RasGRP4 and 3 also contribute to signaling downstream of preTCR. Note that distinct stages of T cell development are taking places in different anatomical parts of thymus. Also, dynamic patterns of RasGRP1 expression are highlighted-RasGRP1’s expression is low in early subsets (DN cells), increases significantly in DP cells and peaks in SP thymocytes to drop again in peripheral T cells.
Fig.4  Overview of B cell development and RasGRP expression. Early B cell progenitors in the bone marrow undergo genetic rearrangement of their immunoglobulin genes, leading to expression of a unique B cell receptor on the surface each B cell. The B cell receptor mediates a series of self antigen-driven checkpoints that progressively eliminate autoreactive clones from the B cell repertoire. As immature B cells progress to a transitional stage, they exit the bone marrow, enter the circulation and migrate to the spleen where their selection and differentiation continues. Splenic B cells differentiate into follicular or marginal zone cells, and mature follicular B cells can recirculate throughout the body and populate the bone marrow and lymph nodes.
Fig.5  Multiple receptor systems couple to different RasGRP proteins. Scheme is showing different receptors which couple to distinct members of RasGRP family. RasGRP1 signals downstream of antigen receptors such as preTCR, TCR, BCR but also from cytokine receptors including G-CSFR and IL7R. More recently it has also been shown that RasGRP1 also couples to Fc binding receptor as well as to GPCR such as CXCR4. RasGRP2 is mainly activated downstream of GPCR such as thrombin receptor. RasGRP3, similarly to RasGRP1 is engaged after antigen receptor triggering, but can also function downstream of receptor tyrosine kinases such as cMet (HGFR) or EGFR and cytokine receptor (GM-SCF). Finally, fMLP receptor (GPCR), FcR, preTCR and GM-SCF can all activated RasGRP4. preTCR-pre T cell receptor; TCR-T cell receptor; BCR-B cell receptor; G-CSFR- granulocyte colony stimulating factor receptor; GM-CSFR- granulocyte-macrophage colony stimulating factor receptor; EGFR- Epidermal growth factor receptor; HGFR- hepatocyte growth factor receptor; GPCR- G protein coupled receptor.
Fig.6  Dysregulated RasGRP1 cooperates with cytokine receptor input in T cell leukemogenesis. T cell leukemia cells expand in the bone marrow in response to growth factors like interleukin 7 (IL7 in green) and take over the space in the cavity (uniform purple cells in the illustration). This expansion leads to a loss of the variety in bone marrow cells, such as blood stem cells (in pink), red blood cells (in red) and fat cells (in yellow) that are normally seen in the bone marrow. The Hartzell et al. study describes how two related, but distinct, genetic alterations in T cell leukemia cells, mutated K-Ras or dysregulated Rasgrp1, both lead to T cell leukemia by responding to IL7 and other signals in different manners.
1 Abel E L, Angel J M, Kiguchi K, DiGiovanni J (2009). Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat Protoc , 4(9): 1350–1362
doi: 10.1038/nprot.2009.120 pmid:19713956
2 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
doi: 10.1074/jbc.M112.360388 pmid:22511759
3 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
doi: 10.1038/nrm3255 pmid:22189424
4 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
5 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
doi: 10.1073/pnas.0407468101 pmid:15545601
6 Aifantis I, Raetz E, Buonamici S (2008). Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol , 8(5): 380–390
doi: 10.1038/nri2304 pmid:18421304
7 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
doi: 10.1084/jem.184.1.9 pmid:8691153
8 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). Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood , 111(8): 4322-4328
doi: 10.1182/blood-2007-06-095075 pmid:18172006
9 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
doi: 10.1080/10428190400027852 pmid:16019476
10 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
pmid:15590396
11 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
doi: 10.1084/jem.20040789 pmid:15353558
12 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
doi: 10.1091/mbc.E06-10-0932 pmid:17567957
13 Bell J J, Bhandoola A (2008). The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature , 452(7188): 764-767
doi: 10.1038/nature06840 pmid:18401411
14 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
doi: 10.1016/S0952-7915(99)80025-9 pmid:10322153
15 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
doi: 10.1172/JCI30575 pmid:17492052
16 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
doi: 10.1182/blood-2011-03-343947 pmid:21828136
17 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
doi: 10.1038/nature01806 pmid:12845332
18 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
doi: 10.1016/j.cell.2007.05.018 pmid:17540168
19 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
doi: 10.1074/jbc.M109.009514 pmid:19700408
20 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
doi: 10.1016/j.cub.2006.09.033 pmid:17084704
21 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
doi: 10.1124/mol.66.1.76 pmid:15213298
22 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
doi: 10.1038/nri2133 pmid:17641666
23 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
doi: 10.1189/jlb.0110049 pmid:20413728
24 Chakraborty A K, Roose J P (2013). Biochemical heterogeneity and developmental varieties in T-cell leukemia. Cell Cycle , 12(10): 1480-1481
doi: 10.4161/cc.24858 pmid:23652920
25 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
doi: 10.1182/blood-2006-08-039883 pmid:17363738
26 Chang L, Karin M (2001). Mammalian MAP kinase signalling cascades. Nature , 410(6824): 37-40
doi: 10.1038/35065000 pmid:11242034
27 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
doi: 10.1158/0008-5472.CAN-08-4884 pmid:19351820
28 Chung J B, Silverman M, Monroe J G (2003). Transitional B cells: step by step towards immune competence. Trends Immunol , 24(6): 343-349
doi: 10.1016/S1471-4906(03)00119-4 pmid:12810111
29 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
doi: 10.1182/blood-2008-02-139733 pmid:18544684
30 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
doi: 10.1074/jbc.M006087200 pmid:10918068
31 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
doi: 10.1038/nrc2047 pmid:17251918
32 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
33 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
doi: 10.1016/S1470-2045(08)70314-0 pmid:19147408
34 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
doi: 10.1038/nm1098 pmid:15334074
35 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
doi: 10.1073/pnas.1001064107 pmid:20194733
36 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
doi: 10.1016/j.molimm.2004.04.008 pmid:15219998
37 Daniels M A, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, Werlen G, Holl?nder G A, Gascoigne N R J, Palmer E (2006). Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature , 444(7120): 724-729
doi: 10.1038/nature05269 pmid:17086201
38 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
doi: 10.1016/j.cell.2008.11.051 pmid:19167334
39 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
doi: 10.1182/blood-2009-10-246967 pmid:20203268
40 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
41 DeFranco A L (2000). B-cell activation 2000. Immunol Rev , 176: 5-9
pmid:11043763
42 Diaz-Flores E,, Hana Goldschmidt, Philippe Depeille, Victor Ng, Kimberly Krisman, Michael Crone, Michael R. Burgess, Olusegun Williams, BenjaminHouseman, 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)
43 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
doi: 10.1073/pnas.092284399 pmid:12195013
44 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
doi: 10.2353/ajpath.2009.090036 pmid:19497993
45 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
doi: 10.1038/79766 pmid:11017103
46 Dührsen U, Stahl J, Gough N M (1990). In vivo transformation of factor-dependent hemopoietic cells: role of intracisternal A-particle transposition for growth factor gene activation. EMBO J , 9(4): 1087-1096
pmid:2108861
47 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
doi: 10.1126/science.280.5366.1082 pmid:9582122
48 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
pmid:10807788
49 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
pmid:1704804
50 Feldman B J, Feldman D (2001). The development of androgen-independent prostate cancer. Nat Rev Cancer , 1(1): 34-45
doi: 10.1038/35094009 pmid:11900250
51 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
doi: 10.1016/S1535-6108(02)00018-1 pmid:12086890
52 Feske S (2007). Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol , 7(9): 690-702
doi: 10.1038/nri2152 pmid:17703229
53 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
54 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
doi: 10.1371/journal.pone.0038796 pmid:22719950
55 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
doi: 10.1182/blood-2007-03-077628 pmid:17702895
56 Gifford J L, Walsh M P, Vogel H J (2007). Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs. Biochem J , 405(2): 199-221
doi: 10.1042/BJ20070255 pmid:17590154
57 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
doi: 10.1371/journal.pone.0053300 pmid:23308188
58 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
doi: 10.1038/342385a0 pmid:2586609
59 Grabarek Z (2006). Structural basis for diversity of the EF-hand calcium-binding proteins. J Mol Biol , 359(3): 509-525
doi: 10.1016/j.jmb.2006.03.066 pmid:16678204
60 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
doi: 10.1038/nrc1880 pmid:16612405
61 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
doi: 10.1038/sj.leu.2404302 pmid:16826225
62 Grisendi S, Mecucci C, Falini B, Pandolfi P P (2006). Nucleophosmin and cancer. Nat Rev Cancer , 6(7): 493-505
doi: 10.1038/nrc1885 pmid:16794633
63 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
doi: 10.1074/jbc.M314273200 pmid:14970203
64 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
doi: 10.1182/blood-2009-02-206722 pmid:19458356
65 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
doi: 10.1126/scisignal.2003848 pmid:23532335
66 Hertz M, Nemazee D (1997). BCR ligation induces receptor editing in IgM+IgD- bone marrow B cells in vitro. Immunity , 6(4): 429-436
doi: 10.1016/S1074-7613(00)80286-1 pmid:9133422
67 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
pmid:1620132
68 Janas M L, Turner M (2011). Interaction of Ras with P110 is required for thymic-selection in the mouse. J Immunol (Baltimore, Md: 1950) 187: 4667-4675
69 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
doi: 10.1042/BJ20070294 pmid:17523924
70 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)
71 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
doi: 10.1016/S0145-2126(98)00146-5 pmid:10071127
72 Kawasaki H, Springett G M, 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
doi: 10.1073/pnas.95.22.13278 pmid:9789079
73 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, G?ttgens B, Grimes H L, M?r?y T (2013). Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell , 23(2): 200-214
doi: 10.1016/j.ccr.2013.01.011 pmid:23410974
74 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
doi: 10.1128/JVI.77.3.2056-2062.2003 pmid:12525640
75 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
doi: 10.1038/nri2669 pmid:19935803
76 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
doi: 10.1038/sj.onc.1208334 pmid:15829980
77 Knudsen B S, Edlund M (2004). Prostate cancer and the met hepatocyte growth factor receptor. Adv Cancer Res , 91: 31-67
doi: 10.1016/S0065-230X(04)91002-0 pmid:15327888
78 Koike K, Matsuda K (2008). Recent advances in the pathogenesis and management of juvenile myelomonocytic leukaemia. Br J Haematol , 141(5): 567-575
doi: 10.1111/j.1365-2141.2008.07104.x pmid:18422786
79 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
pmid:22951309
80 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
doi: 10.1073/pnas.1104295108 pmid:21746917
81 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
doi: 10.1128/MCB.00317-12 pmid:22586275
82 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
83 Kurosaki T (1999). Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol , 17(1): 555-592
doi: 10.1146/annurev.immunol.17.1.555 pmid:10358768
84 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
doi: 10.1016/S0092-8674(00)80373-6 pmid:9323135
85 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
doi: 10.1038/nature08279 pmid:19727076
86 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
pmid:9712025
87 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
doi: 10.1016/j.cell.2012.03.031 pmid:22579283
88 Lee S H, Yun S, Lee J, Kim M J, Piao Z-H, Jeong M, Chung J W, Kim T-D, 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
89 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
90 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
doi: 10.1038/ni.2016 pmid:21441934
91 Limnander A, Weiss A (2011). Ca-dependent Ras/Erk signaling mediates negative selection of autoreactive B cells. Small GTPases , 2(5): 282-288
doi: 10.4161/sgtp.2.5.17794 pmid:22292132
92 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
pmid:10779365
93 Lorenzo P S, Kung J W, 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
pmid:11221888
94 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
doi: 10.1158/0008-5472.CAN-07-2375 pmid:17974959
95 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
doi: 10.1038/nature05886 pmid:17515920
96 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
doi: 10.1016/S0092-8674(00)80912-5 pmid:9458042
97 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
doi: 10.1038/ng950 pmid:12185366
98 Mor A, Philips M R (2006). Compartmentalized Ras/MAPK signaling. Annu Rev Immunol , 24(1): 771-800
doi: 10.1146/annurev.immunol.24.021605.090723 pmid:16551266
99 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
doi: 10.1038/ni.2008 pmid:21399638
100 Norment A M, Bogatzki L Y, Klinger M, Ojala E W, Bevan M J, 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
101 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
doi: 10.1084/jem.20031547 pmid:14676298
102 Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T,βHarada H,βKitamura T (2011). Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis. Leukemia
pmid:22116551
103 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
doi: 10.1158/0008-5472.CAN-06-3080 pmid:17210708
104 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 gamma-secretase inhibitors. Leukemia , 20(7): 1279-1287
doi: 10.1038/sj.leu.2404258 pmid:16688224
105 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
106 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, Zú?iga-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
doi: 10.1038/nm1636 pmid:17873882
107 Pawson T, Linding R (2008). Network medicine. FEBS Lett , 582(8): 1266-1270
doi: 10.1016/j.febslet.2008.02.011 pmid:18282479
108 Perez-Losada J, Balmain A (2003). Stem-cell hierarchy in skin cancer. Nat Rev Cancer , 3(6): 434-443
doi: 10.1038/nrc1095 pmid:12778133
109 Pieters R, Carroll W L, (2008). Biology and treatment of acute lymphoblastic leukemia. Pediatric Clinics of NA 24: 1-20
110 Pillai S (1999). The chosen few? Positive selection and the generation of naive B lymphocytes. Immunity , 10(5): 493-502
doi: 10.1016/S1074-7613(00)80049-7 pmid:10367895
111 Pillai S, Cariappa A (2009). The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol , 9(11): 767-777
doi: 10.1038/nri2656 pmid:19855403
112 Pillai S, Cariappa A, Moran S T (2004). Positive selection and lineage commitment during peripheral B-lymphocyte development. Immunol Rev , 197(1): 206-218
doi: 10.1111/j.0105-2896.2003.097.x pmid:14962197
113 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
doi: 10.1016/S1074-7613(02)00451-X pmid:12433368
114 Rajalingam K, Schreck R, Rapp U R, Albert S (2007). Ras oncogenes and their downstream targets. Biochim Biophys Acta , 1773(8): 1177-1195
doi: 10.1016/j.bbamcr.2007.01.012 pmid:17428555
115 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
doi: 10.1074/jbc.M308240200 pmid:14532295
116 Ratushny V, Gober M D, Hick R, Ridky T W, Seykora J T (2012). From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J Clin Invest , 122(2): 464-472
doi: 10.1172/JCI57415 pmid:22293185
117 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
doi: 10.1074/jbc.M111330200 pmid:11880369
118 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
doi: 10.1128/MCB.24.24.10515-10528.2004 pmid:15572660
119 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
pmid:7516889
120 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
doi: 10.1128/MCB.25.11.4426-4441.2005 pmid:15899849
121 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
122 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
doi: 10.1128/MCB.00912-07 pmid:17923690
123 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-O-tetradecanoylphorbol-13-acetate in epidermal keratinocytes. J Biol Chem , 285(21): 15724-15730
doi: 10.1074/jbc.M109.100016 pmid:20308057
124 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
doi: 10.1158/0008-5472.CAN-10-3606 pmid:21593192
125 Smith-Garvin J E, Koretzky G A, Jordan M S (2009). T cell activation. Annu Rev Immunol , 27(1): 591-619
doi: 10.1146/annurev.immunol.021908.132706 pmid:19132916
126 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
doi: 10.1016/j.exphem.2008.09.008 pmid:19100522
127 Starr T K, Jameson S C, Hogquist K A (2003). Positive and negative selection of T cells. Annu Rev Immunol , 21(1): 139-176
doi: 10.1146/annurev.immunol.21.120601.141107 pmid:12414722
128 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
doi: 10.1182/blood-2011-03-342352 pmid:21652673
129 Stone J C (2011). Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells. Genes &amp. Cancer , 2: 320-334
130 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
doi: 10.1038/nature11183 pmid:22763439
131 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
doi: 10.1111/j.0105-2896.2004.0102.x pmid:14962194
132 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
doi: 10.1016/j.ccr.2012.02.029 pmid:22516257
133 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
doi: 10.1038/emboj.2012.167 pmid:22728827
134 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
doi: 10.1038/ng949 pmid:12185365
135 Tazmini G, Beaulieu N, Woo A, Zahedi B, Goulding R E, Kay R J (2009). Membrane localization of RasGRP1 is controlled by an EF-hand, and by the GEF domain. Biochim Biophys Acta , 1793(3): 447-461
doi: 10.1016/j.bbamcr.2008.12.019 pmid:19168098
136 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
doi: 10.1182/blood-2002-11-3621 pmid:12730099
137 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
doi: 10.1126/science.272.5269.1804 pmid:8650582
138 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
doi: 10.1016/S0167-5699(98)01440-6 pmid:10322300
139 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
doi: 10.1038/ng.796 pmid:21441929
140 Vetter I R, Wittinghofer A (2001). The guanine nucleotide-binding switch in three dimensions. Science , 294(5545): 1299-1304
doi: 10.1126/science.1062023 pmid:11701921
141 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
doi: 10.1038/nrc2960 pmid:21102635
142 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
doi: 10.1126/science.1235122 pmid:23539594
143 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
pmid:10815901
144 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
doi: 10.1038/nature06839 pmid:18401412
145 Ward A F, Braun B S, Shannon K M (2012). Targeting oncogenic Ras signaling in hematologic malignancies. Blood , 120(17): 3397-3406
doi: 10.1182/blood-2012-05-378596 pmid:22898602
146 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
doi: 10.1007/s12185-009-0299-0 pmid:19350351
147 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
doi: 10.1126/science.1102160 pmid:15472075
148 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,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
149 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
doi: 10.1038/nature11249 pmid:22763448
150 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
doi: 10.1182/blood.V97.8.2434 pmid:11290608
151 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
doi: 10.1074/jbc.M003414200 pmid:10835426
152 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
doi: 10.1158/0008-5472.CAN-09-4729 pmid:20876802
153 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: 4590-4600
154 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
doi: 10.1074/jbc.M202575200 pmid:11956218
155 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
doi: 10.1126/scisignal.2001592 pmid:21505187
156 Yasuda T, Kurosaki T (2008). Regulation of lymphocyte fate by Ras/ERK signals. Cell Cycle , 7(23): 3634-3640
doi: 10.4161/cc.7.23.7103 pmid:19029810
157 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
doi: 10.1016/j.immuni.2008.02.015 pmid:18356083
158 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
doi: 10.1016/S0925-5710(98)00015-2 pmid:9695411
159 Young D C, Griffin J D (1986). Autocrine secretion of GM-CSF in acute myeloblastic leukemia. Blood , 68(5): 1178-1181
pmid:3490289
160 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
doi: 10.1074/jbc.M110.189605 pmid:21285350
161 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
doi: 10.1038/ng.924 pmid:21892159
162 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
doi: 10.1038/nature10725 pmid:22237106
163 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
doi: 10.1182/blood-2004-10-3916 pmid:15657177
164 Zhu M, Fuller D M, 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
doi: 10.1074/jbc.M111.320580 pmid:22262848
165 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
doi: 10.1038/nature11311 pmid:22902503
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