Bimodal expression of Sprouty2 during the cell cycle is mediated by phase-specific Ras/MAPK and c-Cbl activities.
Sprouty2 is an important inhibitor of cell proliferation and signal transduction. In this study, we found a bimodal expression of Sprouty2 protein during cell cycle progression after exit from quiescence, whereas elevated Sprouty4 expression in the G1 phase stayed high throughout the rest of the cell cycle. Induction of the mitogen-activated protein kinase via activated Ras was crucial for increased Sprouty2 expression at the G0/G1 transition. Following the first peak, accelerated proteasomal protein degradation caused a transient attenuation of Sprouty2 abundance during late G1. Since the decline in its expression was abolished by dominant negative c-Cbl and the timely restricted interaction between Sprouty2 and c-Cbl disappeared at the second peak of Sprouty2 expression, we conclude that the second phase in the cell cycle-specific expression profile of Sprouty2 is solely dependent on ubiquitination by c-Cbl. Our results suggest that Sprouty2 abundance is the result of strictly coordinated activities of Ras and c-Cbl.
Mayer
Christoph-Erik
CE
Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria. christoph-erik.mayer@meduniwien.ac.at
Haigl
Barbara
B
Jantscher
Florian
F
Siegwart
Gerald
G
Grusch
Michael
M
Berger
Walter
W
Sutterlüty
Hedwig
H
D002453:Cell Cycle / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000473:pathology
Cancer Res. 2006 Feb 15;66(4):2048-58
16489004
EMBO Rep. 2005 Jul;6(7):635-41
15962011
Mol Cancer Res. 2008 Mar;6(3):468-82
18337453
J Biol Chem. 2007 Mar 23;282(12):9117-26
17255109
Cancer Res. 2004 Sep 1;64(17):6127-36
15342396
Cancer Res. 2009 Jan 1;69(1):235-42
19118008
Mol Cell Biol. 2006 Mar;26(5):1898-907
16479008
J Biol Chem. 2001 Sep 28;276(39):36804-8
11495895
Cell. 1997 May 2;89(3):457-67
9150145
J Biol Chem. 2001 Jun 22;276(25):22742-7
11279012
Mol Cancer Res. 2007 May;5(5):509-20
17510316
Cell. 2003 Sep 19;114(6):715-25
14505571
Nat Rev Mol Cell Biol. 2003 Nov;4(11):855-64
14625536
Mol Cell Neurosci. 2000 Jan;15(1):22-35
10662503
J Biol Chem. 2006 Feb 24;281(8):4816-22
16371366
Nucleic Acids Res. 1998 Nov 1;26(21):4989-95
9776764
J Biol Chem. 2001 Feb 9;276(6):4128-33
11053436
Mol Cell. 2001 Feb;7(2):355-65
11239464
Mol Biol Cell. 2004 May;15(5):2176-88
15004239
Curr Biol. 2003 Feb 18;13(4):308-14
12593796
J Cell Biochem. 2007 Jan 1;100(1):151-60
16888801
Biochem Biophys Res Commun. 2007 Jan 26;352(4):896-902
17156747
Oncogene. 2004 Jul 1;23(30):5193-202
15122328
Trends Cell Biol. 2006 Jan;16(1):45-54
16337795
Cancer Res. 2004 Jul 15;64(14):4728-35
15256439
J Biol Chem. 2001 Feb 23;276(8):5866-75
11053437
Genes Dev. 2007 Mar 15;21(6):694-707
17369402
Biochem Biophys Res Commun. 2001 Aug 3;285(5):1084-8
11478764
Mech Dev. 1999 Mar;81(1-2):213-6
10330503
Curr Biol. 2003 Feb 18;13(4):297-307
12593795
J Biol Chem. 2001 Dec 7;276(49):46460-8
11585837
Nat Rev Mol Cell Biol. 2001 Apr;2(4):294-307
11283727
Curr Biol. 1999 Feb 25;9(4):219-22
10074434
Nat Cell Biol. 1999 Aug;1(4):207-14
10559918
J Biol Chem. 2004 May 28;279(22):22992-5
15031289
Development. 1999 Oct;126(20):4465-75
10498682
J Biol Chem. 2010 Jan 1;285(1):255-64
19864419
Prostate. 2006 May 1;66(6):613-24
16388505
Cell. 1998 Jan 23;92(2):253-63
9458049
Mech Dev. 2001 Apr;102(1-2):81-94
11287183
Cell. 2000 Jan 7;100(1):57-70
10647931
Gene. 2003 Dec 11;322:175-85
14644509
Mech Dev. 2000 Mar 1;91(1-2):361-4
10704865
Genes Dev. 2001 May 1;15(9):1152-66
11331610
Cancer Cell. 2006 Dec;10(6):459-72
17157787
Nat Cell Biol. 2002 Feb;4(2):170-4
11802165
J Biol Chem. 2005 May 20;280(20):19625-34
15705594
Oncogene. 2005 Mar 24;24(13):2166-74
15735753
J Cell Biol. 2001 Mar 5;152(5):1087-98
11238463