title: RasGRP Ras guanine nucleotide exchange factors in cancer.
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 forRasgrpgenes. 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 mechanism 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.
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Ksionda
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Limnander
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
keywords: Ras; RasGRP; cancer; lymphocytes; receptor; signaling
references.citation: Blood. 2007 Nov 15;110(10):3682-90
references.pmid: 17702895
references.citation: Mol Immunol. 2004 Jul;41(6-7):599-613
references.pmid: 15219998
references.citation: Exp Hematol. 1994 Jul;22(7):593-8
references.pmid: 7516889
references.citation: Nat Rev Cancer. 2007 Feb;7(2):118-29
references.pmid: 17251918
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1177-95
references.pmid: 17428555
references.citation: Front Immunol. 2013 Sep 04;4:239
references.pmid: 24027568
references.citation: Science. 2001 Nov 9;294(5545):1299-304
references.pmid: 11701921
references.citation: Nat Genet. 2002 Sep;32(1):153-9
references.pmid: 12185366
references.citation: J Leukoc Biol. 2010 Aug;88(2):313-9
references.pmid: 20413728
references.citation: Nature. 2009 Sep 17;461(7262):411-4
references.pmid: 19727076
references.citation: Annu Rev Immunol. 2006;24:771-800
references.pmid: 16551266
references.citation: Cancer Res. 2007 Nov 1;67(21):10190-7
references.pmid: 17974959
references.citation: Cancer Cell. 2012 Apr 17;21(4):459-72
references.pmid: 22516257
references.citation: Immunol Rev. 2004 Feb;197:206-18
references.pmid: 14962197
references.citation: Science. 2004 Oct 8;306(5694):269-71
references.pmid: 15472075
references.citation: Immunol Rev. 2004 Feb;197:161-78
references.pmid: 14962194
references.citation: Nature. 2008 Apr 10;452(7188):764-7
references.pmid: 18401411
references.citation: Mol Pharmacol. 2000 May;57(5):840-6
references.pmid: 10779365
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18261-6
references.pmid: 17114293
references.citation: Blood. 1990 Apr 15;75(8):1684-90
references.pmid: 2183888
references.citation: Oncogene. 2011 Nov 10;30(45):4590-4600
references.pmid: 21602881
references.citation: Blood. 2012 Oct 25;120(17):3397-406
references.pmid: 22898602
references.citation: Nature. 2006 Dec 7;444(7120):724-9
references.pmid: 17086201
references.citation: Cancer Res. 2001 Feb 1;61(3):943-9
references.pmid: 11221888
references.citation: Nature. 2012 Jul 26;487(7408):500-4
references.pmid: 22763439
references.citation: Leukemia. 2006 Jul;20(7):1279-87
references.pmid: 16688224
references.citation: Nat Rev Cancer. 2010 Dec;10(12):842-57
references.pmid: 21102635
references.citation: Immunity. 2008 Apr;28(4):499-508
references.pmid: 18356083
references.citation: Blood. 2008 Sep 1;112(5):1696-703
references.pmid: 18544684
references.citation: J Biol Chem. 2011 Apr 8;286(14):12712-23
references.pmid: 21285350
references.citation: J Mol Biol. 2006 Jun 9;359(3):509-25
references.pmid: 16678204
references.citation: Exp Hematol. 2009 Jan;37(1):122-134
references.pmid: 19100522
references.citation: Int J Hematol. 1998 Jun;67(4):379-87
references.pmid: 9695411
references.citation: Mol Pharmacol. 2004 Jul;66(1):76-84
references.pmid: 15213298
references.citation: Small GTPases. 2011 Sep;2(5):282-288
references.pmid: 22292132
references.citation: Nat Rev Cancer. 2006 Jul;6(7):493-505
references.pmid: 16794633
references.citation: J Immunol. 2011 Nov 1;187(9):4667-75
references.pmid: 21930962
references.citation: PLoS One. 2012;7(6):e38796
references.pmid: 22719950
references.citation: Mol Cell Biol. 1992 Jul;12(7):3305-12
references.pmid: 1620132
references.citation: J Biol Chem. 2012 Jun 8;287(24):20047-55
references.pmid: 22511759
references.citation: Science. 1996 Jun 21;272(5269):1804-8
references.pmid: 8650582
references.citation: Science. 2013 Mar 29;339(6127):1546-58
references.pmid: 23539594
references.citation: Cell. 1998 Jan 23;92(2):173-82
references.pmid: 9458042
references.citation: Leukemia. 2012 May;26(5):1038-45
references.pmid: 22116551
references.citation: Trends Immunol. 2013 Jun;34(6):259-68
references.pmid: 23506953
references.citation: J Immunol. 2009 Dec 15;183(12):7931-8
references.pmid: 19933860
references.citation: J Biol Chem. 2000 Aug 18;275(33):25488-93
references.pmid: 10835426
references.citation: Mol Biol Cell. 2007 Aug;18(8):3156-68
references.pmid: 17567957
references.citation: Blood. 1986 Nov;68(5):1178-81
references.pmid: 3490289
references.citation: Annu Rev Immunol. 2009;27:591-619
references.pmid: 19132916
references.citation: Nat Rev Cancer. 2006 May;6(5):347-59
references.pmid: 16612405
references.citation: Cell. 1997 Sep 19;90(6):1073-83
references.pmid: 9323135
references.citation: Clin Cancer Res. 2000 May;6(5):1804-10
references.pmid: 10815901
references.citation: Blood. 2001 Apr 15;97(8):2434-9
references.pmid: 11290608
references.citation: Mol Cell Biol. 2012 Jul;32(14):2748-59
references.pmid: 22586275
references.citation: Blood. 2008 Apr 15;111(8):4322-8
references.pmid: 18172006
references.citation: J Immunol. 2011 Sep 15;187(6):3177-85
references.pmid: 21856938
references.citation: Cell Cycle. 2013 May 15;12(10):1480-1
references.pmid: 23652920
references.citation: Blood. 2003 Aug 15;102(4):1414-20
references.pmid: 12730099
references.citation: Mol Cell Biol. 2007 Apr;27(7):2732-45
references.pmid: 17283063
references.citation: Adv Cancer Res. 2004;91:31-67
references.pmid: 15327888
references.citation: Nat Immunol. 2011 Apr;12(4):352-61
references.pmid: 21399638
references.citation: Sci Signal. 2011 Apr 19;4(169):ra25
references.pmid: 21505187
references.citation: Biochim Biophys Acta. 2005 Nov 25;1756(2):127-44
references.pmid: 16139957
references.citation: PLoS One. 2013;8(1):e53300
references.pmid: 23308188
references.citation: FEBS Lett. 2008 Apr 9;582(8):1266-70
references.pmid: 18282479
references.citation: Leuk Lymphoma. 2005 Apr;46(4):483-95
references.pmid: 16019476
references.citation: Cell. 2009 Jan 23;136(2):337-51
references.pmid: 19167334
references.citation: Oncogene. 2005 Apr 14;24(16):2695-704
references.pmid: 15829980
references.citation: Mol Cell Biol. 2004 Dec;24(24):10515-28
references.pmid: 15572660
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12407-12
references.pmid: 21746917
references.citation: Immunol Today. 1999 May;20(5):217-20
references.pmid: 10322300
references.citation: Immunity. 1999 May;10(5):493-502
references.pmid: 10367895
references.citation: Blood. 2000 May 15;95(10):3199-203
references.pmid: 10807788
references.citation: Nature. 2008 Apr 10;452(7188):768-72
references.pmid: 18401412
references.citation: J Biol Chem. 2002 Jul 12;277(28):25756-74
references.pmid: 11956218
references.citation: Cell Cycle. 2008 Dec;7(23):3634-40
references.pmid: 19029810
references.citation: Nat Rev Immunol. 2007 Sep;7(9):690-702
references.pmid: 17703229
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16612-7
references.pmid: 15545601
references.citation: Cell. 2012 May 11;149(4):780-94
references.pmid: 22579283
references.citation: Am J Pathol. 2009 Jul;175(1):392-9
references.pmid: 19497993
references.citation: Cancer Res. 2007 Jan 1;67(1):276-80
references.pmid: 17210708
references.citation: Biochim Biophys Acta. 2009 Mar;1793(3):447-61
references.pmid: 19168098
references.citation: J Immunol. 2003 Feb 1;170(3):1141-9
references.pmid: 12538669
references.citation: Lancet Oncol. 2009 Feb;10(2):147-56
references.pmid: 19147408
references.citation: Nat Genet. 2011 Sep 04;43(10):932-9
references.pmid: 21892159
references.citation: Curr Opin Immunol. 1999 Apr;11(2):143-51
references.pmid: 10322153
references.citation: J Biol Chem. 2012 Mar 9;287(11):8135-43
references.pmid: 22262848
references.citation: J Biol Chem. 2000 Oct 13;275(41):32260-7
references.pmid: 10918068
references.citation: Blood. 2007 Jul 1;110(1):278-86
references.pmid: 17363738
references.citation: Nat Rev Cancer. 2003 Jun;3(6):434-43
references.pmid: 12778133
references.citation: Nat Rev Immunol. 2007 Aug;7(8):633-43
references.pmid: 17641666
references.citation: Nat Rev Mol Cell Biol. 2011 Dec 22;13(1):39-51
references.pmid: 22189424
references.citation: J Biol Chem. 2010 May 21;285(21):15724-30
references.pmid: 20308057
references.citation: J Virol. 2003 Feb;77(3):2056-62
references.pmid: 12525640
references.citation: Nat Immunol. 2000 Oct;1(4):317-21
references.pmid: 11017103
references.citation: Cancer Cell. 2002 Feb;1(1):75-87
references.pmid: 12086890
references.citation: Mol Cell Biol. 2007 Dec;27(23):8127-42
references.pmid: 17923690
references.citation: Nature. 2001 Mar 1;410(6824):37-40
references.pmid: 11242034
references.citation: Int J Hematol. 2009 May;89(4):470-481
references.pmid: 19350351
references.citation: Nat Protoc. 2009;4(9):1350-62
references.pmid: 19713956
references.citation: Biochem J. 2007 Sep 1;406(2):223-36
references.pmid: 17523924
references.citation: Leukemia. 2006 Sep;20(9):1496-510
references.pmid: 16826225
references.citation: Cancer Res. 2011 Jul 15;71(14):4780-9
references.pmid: 21593192
references.citation: Annu Rev Immunol. 1999;17:555-92
references.pmid: 10358768
references.citation: Trends Immunol. 2003 Jun;24(6):343-9
references.pmid: 12810111
references.citation: J Biol Chem. 2009 Oct 16;284(42):28522-32
references.pmid: 19700408
references.citation: Nat Immunol. 2011 May;12(5):425-33
references.pmid: 21441934
references.citation: Blood. 2011 Jul 28;118(4):1113-20
references.pmid: 21652673
references.citation: Cancer Cell. 2013 Feb 11;23(2):200-14
references.pmid: 23410974
references.citation: Genes Dev. 2006 Aug 1;20(15):2096-109
references.pmid: 16847353
references.citation: Blood. 2009 Jul 16;114(3):647-50
references.pmid: 19458356
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11796-801
references.pmid: 12195013
references.citation: Leuk Res. 1999 Feb;23(2):115-26
references.pmid: 10071127
references.citation: J Immunol. 2005 Dec 1;175(11):7179-84
references.pmid: 16301621
references.citation: EMBO J. 2012 Jul 18;31(14):3118-29
references.pmid: 22728827
references.citation: Cell. 2007 Jun 1;129(5):865-77
references.pmid: 17540168
references.citation: Genes Cancer. 2011 Mar;2(3):320-34
references.pmid: 21779502
references.citation: Nat Rev Immunol. 2009 Nov;9(11):767-77
references.pmid: 19855403
references.citation: Haematologica. 2004 Dec;89(12):1459-67
references.pmid: 15590396
references.citation: Blood. 2005 May 1;105(9):3648-54
references.pmid: 15657177
references.citation: Curr Biol. 2006 Nov 7;16(21):2173-9
references.pmid: 17084704
references.citation: Annu Rev Immunol. 2003;21:139-76
references.pmid: 12414722
references.citation: Nat Genet. 2011 May;43(5):470-5
references.pmid: 21441929
references.citation: Sci Signal. 2013 Mar 26;6(268):ra21
references.pmid: 23532335
references.citation: Nature. 2012 Jul 26;487(7408):505-9
references.pmid: 22763448
references.citation: Science. 1998 May 15;280(5366):1082-6
references.pmid: 9582122
references.citation: J Exp Med. 1996 Jul 1;184(1):9-18
references.pmid: 8691153
references.citation: J Biol Chem. 2002 Aug 23;277(34):30508-14
references.pmid: 11880369
references.citation: Pediatr Clin North Am. 2008 Feb;55(1):1-20, ix
references.pmid: 18242313
references.citation: J Clin Invest. 2012 Feb;122(2):464-72
references.pmid: 22293185
references.citation: Immunity. 1997 Apr;6(4):429-36
references.pmid: 9133422
references.citation: Blood. 1991 Mar 1;77(5):925-9
references.pmid: 1704804
references.citation: Mol Cell Biol. 2005 Jun;25(11):4426-41
references.pmid: 15899849
references.citation: Nat Med. 2007 Oct;13(10):1203-10
references.pmid: 17873882
references.citation: Cancer Res. 2009 Apr 15;69(8):3520-8
references.pmid: 19351820
references.citation: Nat Rev Immunol. 2009 Dec;9(12):833-44
references.pmid: 19935803
references.citation: Immunity. 2002 Nov;17(5):617-27
references.pmid: 12433368
references.citation: Nature. 2003 Aug 7;424(6949):694-8
references.pmid: 12845332
references.citation: Nature. 2007 Jun 21;447(7147):966-71
references.pmid: 17515920
references.citation: Nat Rev Immunol. 2008 May;8(5):380-90
references.pmid: 18421304
references.citation: J Immunol. 1998 Aug 15;161(4):1637-44
references.pmid: 9712025
references.citation: Blood. 2010 May 13;115(19):3970-9
references.pmid: 20203268
references.citation: J Exp Med. 2004 Sep 6;200(5):659-69
references.pmid: 15353558
references.citation: EMBO J. 1990 Apr;9(4):1087-96
references.pmid: 2108861
references.citation: J Biol Chem. 2004 May 7;279(19):19523-30
references.pmid: 14970203
references.citation: Blood. 2011 Oct 27;118(17):4646-56
references.pmid: 21828136
references.citation: Sci Signal. 2013 Dec 03;6(304):ra105
references.pmid: 24300897
references.citation: Nat Genet. 2002 Sep;32(1):166-74
references.pmid: 12185365
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5106-11
references.pmid: 20194733
references.citation: J Clin Invest. 2007 Jun;117(6):1699-707
references.pmid: 17492052
references.citation: Nat Rev Cancer. 2001 Oct;1(1):34-45
references.pmid: 11900250
references.citation: Immunol Rev. 2000 Aug;176:5-9
references.pmid: 11043763
references.citation: Nature. 2012 Sep 6;489(7414):160-4
references.pmid: 22902503
references.citation: Cancer Res. 2010 Oct 15;70(20):7905-17
references.pmid: 20876802
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13278-83
references.pmid: 9789079
references.citation: J Biol Chem. 2003 Dec 26;278(52):52792-801
references.pmid: 14532295
references.citation: Biochem J. 2007 Jul 15;405(2):199-221
references.pmid: 17590154
references.citation: Nat Med. 2004 Sep;10(9):982-6
references.pmid: 15334074
references.citation: Br J Haematol. 2008 May;141(5):567-75
references.pmid: 18422786
references.citation: Nature. 2012 Jan 11;481(7380):157-63
references.pmid: 22237106
references.citation: Nature. 1989 Nov 23;342(6248):385-91
references.pmid: 2586609
references.citation: J Exp Med. 2003 Dec 15;198(12):1841-51
references.pmid: 14676298
references.citation: J Immunol. 2003 Jul 1;171(1):390-7
references.pmid: 12817022