Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways.
The Abelson (Abl) family of non-receptor tyrosine kinases has an important role in cell morphogenesis, motility, and proliferation. Although the function of Abl has been extensively studied in leukemia, its role in epithelial cell invasion remains obscure. Using the Drosophila wing epithelium as an in vivo model system, we show that overexpression (activation) of Drosophila Abl (dAbl) causes loss of epithelial apical/basal cell polarity and secretion of matrix metalloproteinases, resulting in a cellular invasion and apoptosis. Our in vivo data indicate that dAbl acts downstream of the Src kinases, which are known regulators of cell adhesion and invasion. Downstream of dAbl, Rac GTPases activate two distinct MAPK pathways: c-Jun N-terminal kinase signaling (required for cell invasion and apoptosis) and ERK signaling (inducing cell proliferation). Activated Abl also increases the activity of Src members through a positive feedback loop leading to signal amplification. Thus, targeting Src-Abl, using available dual inhibitors, could be of therapeutic importance in tumor cell metastasis.
Singh
J
J
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Aaronson
S A
SA
Mlodzik
M
M
D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation; D004330:Drosophila; D016313:Genes, abl / Q000502:physiology*; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D015398:Signal Transduction
Trends Cell Biol. 1999 May;9(5):179-86
10322452
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2721-6
17301221
Genes Dev. 1998 Feb 15;12(4):557-70
9472024
Cell Cycle. 2003 May-Jun;2(3):199-201
12734425
Am J Pathol. 1998 Aug;153(2):333-9
9708792
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7457-62
9636171
Dev Cell. 2004 Sep;7(3):387-99
15363413
Science. 1998 Jan 23;279(5350):509-14
9438836
Nat Immunol. 2005 Dec;6(12):1182-90
16369557
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15394-9
9860979
Development. 1993 Jun;118(2):401-15
8223268
N Engl J Med. 1999 Apr 29;340(17):1330-40
10219069
Cancer Res. 2006 Jun 1;66(11):5648-55
16740702
Oncogene. 2000 Nov 20;19(49):5636-42
11114744
Cell. 1995 Jun 30;81(7):1137-46
7600581
J Med Chem. 2006 Nov 16;49(23):6819-32
17154512
Genes Dev. 1994 Apr 1;8(7):783-95
7926767
Cancer Metastasis Rev. 2006 Mar;25(1):9-34
16680569
Oncogene. 2007 Nov 15;26(52):7313-23
17533370
Biochem Biophys Res Commun. 2008 Sep 26;374(3):512-6
18647596
Adv Cancer Res. 2002;85:51-100
12374288
Curr Biol. 2006 Jun 6;16(11):1139-46
16753569
Cell. 1991 Jul 12;66(1):107-19
2070412
Cancer Res. 2003 Jan 15;63(2):375-81
12543790
EMBO J. 1999 Feb 1;18(3):501-11
9927410
Am J Pathol. 2008 Dec;173(6):1828-38
19008376
J Cell Biol. 1991 Oct;115(2):517-33
1918152
Development. 1995 Mar;121(3):903-14
7720592
Development. 2008 Apr;135(7):1355-64
18305002
Dev Cell. 2006 Jan;10(1):33-44
16399076
Curr Opin Neurobiol. 2000 Feb;10(1):80-7
10679439
Curr Opin Cell Biol. 2003 Dec;15(6):740-6
14644200
Oncogene. 2008 Jul 24;27(32):4385-91
18391983
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11746-50
8524841
Science. 1995 Nov 24;270(5240):1326-31
7481820
J Cell Sci. 2005 Aug 15;118(Pt 16):3717-26
16076903
Breast Cancer Res. 2000;2(3):203-10
11250711
Cancer Treat Rev. 2010 Oct;36(6):492-500
20226597
Nature. 2002 Dec 19-26;420(6917):860-7
12490959
Curr Opin Cell Biol. 2005 Oct;17(5):559-64
16098726
Curr Biol. 2004 Jul 27;14(14):1262-6
15268856
Dev Cell. 2004 Oct;7(4):491-501
15469838
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5466-71
8643598
Oncogene. 2004 Jun 10;23(27):4754-62
15107833
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11858-62
9751755
Jpn J Cancer Res. 2000 Apr;91(4):395-8
10804287
Cell. 2000 Oct 13;103(2):239-52
11057897
Mol Biol Cell. 2008 Jan;19(1):378-93
17959833