Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis.
Angiogenesis contributes to various pathological conditions. Due to the resistance against existing antiangiogenic therapy, an urgent need exists to understand the molecular basis of vessel growth and to identify new targets for antiangiogenic therapy. Here we show that cyclin-dependent kinase 5 (Cdk5), an important modulator of neuronal processes, regulates endothelial cell migration and angiogenesis, suggesting Cdk5 as a novel target for antiangiogenic therapy. Inhibition or knockdown of Cdk5 reduces endothelial cell motility and blocks angiogenesis in vitro and in vivo. We elucidate a specific signaling of Cdk5 in the endothelium; in contrast to neuronal cells, the motile defects upon inhibition of Cdk5 are not caused by an impaired function of focal adhesions or microtubules but by the reduced formation of lamellipodia. Inhibition or down-regulation of Cdk5 decreases the activity of the small GTPase Rac1 and results in a disorganized actin cytoskeleton. Constitutive active Rac1 compensates for the inhibiting effects of Cdk5 knockdown on migration, suggesting that Cdk5 exerts its effects in endothelial cell migration via Rac1. Our work elucidates Cdk5 as a pivotal new regulator of endothelial cell migration and angiogenesis. It suggests Cdk5 as a novel, pharmacologically accessible target for antiangiogenic therapy and provides the basis for a new therapeutic application of Cdk5 inhibitors as antiangiogenic agents.
Liebl
Johanna
J
Center for Drug Research, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
Weitensteiner
Sabine B
SB
Vereb
György
G
Takács
Lili
L
Fürst
Robert
R
Vollmar
Angelika M
AM
Zahler
Stefan
S
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D000077546:Roscovitine; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014470:Umbilical Cord / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D011687:Purines; D042461:Vascular Endothelial Growth Factor A; D000077546:Roscovitine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012694:Serine; D051360:Cyclin-Dependent Kinase 5
Nat Cell Biol. 2009 May;11(5):624-30
19363486
Nat Cell Biol. 2006 Jan;8(1):17-26
16341208
J Cell Biol. 2005 Jun 20;169(6):941-52
15967814
Nature. 2002 Dec 12;420(6916):629-35
12478284
Cancer Res. 2006 Aug 1;66(15):7509-15
16885348
Cancer Cell. 2009 Mar 3;15(3):220-31
19249680
J Cell Sci. 2001 Aug;114(Pt 15):2713-22
11683406
Nat Rev Mol Cell Biol. 2001 Oct;2(10):749-59
11584302
Dev Biol. 2009 Jan 1;325(1):82-93
18992737
Nature. 2010 May 27;465(7297):483-6
20445537
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7570-5
18487454
Cancer Res. 2006 Mar 1;66(5):2708-15
16510591
Cell Prolif. 2009 Feb;42(1):38-48
19143762
J Neurosci. 2004 May 5;24(18):4421-31
15128856
Oncogene. 2001 Oct 1;20(44):6418-34
11607842
Cancer Cell. 2009 Mar 3;15(3):167-70
19249675
Mol Biol Cell. 2003 Aug;14(8):3216-29
12925758
Nature. 2006 Aug 17;442(7104):814-7
16862120
Cancer Cell. 2009 Mar 3;15(3):232-9
19249681
J Biol Chem. 2002 Jun 7;277(23):20783-93
11909854
Mol Cell Biol. 2009 Dec;29(24):6488-99
19822667
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11173-8
8855328
Nat Neurosci. 2007 Jan;10(1):67-76
17143272
J Biol Chem. 2009 Apr 3;284(14):9418-25
19201755
J Cell Sci. 2004 Sep 15;117(Pt 20):4739-48
15331630
Genes Dev. 2004 Apr 15;18(8):862-76
15078817
Blood. 2003 Sep 15;102(6):2099-107
12763936
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11156-60
10500146
Mol Biol Cell. 2007 Nov;18(11):4327-42
17699587
Nat Rev Cancer. 2008 Aug;8(8):592-603
18650835
Eur J Biochem. 1997 Jan 15;243(1-2):527-36
9030781
Mol Biol Cell. 2006 Aug;17(8):3508-20
16760434
J Biol Chem. 2007 Feb 2;282(5):2776-84
17145757
Curr Opin Pharmacol. 2009 Apr;9(2):119-24
18983942
Cell Prolif. 2003 Jun;36(3):131-49
12814430
Brain Pathol. 2007 Jan;17(1):11-23
17493033
J Neurosci. 2008 Aug 13;28(33):8326-37
18701695
Cell Mol Life Sci. 2007 Jul;64(13):1715-22
17497242
Circ Res. 2002 May 3;90(8):874-81
11988488
J Cell Sci. 2008 Aug 1;121(Pt 15):2601-11
18628310
Int J Biochem Cell Biol. 2003 Jan;35(1):39-50
12467646
Oncogene. 2003 Sep 29;22(42):6549-56
14528279
Nat Cell Biol. 2007 Oct;9(10):1110-21
17909522
Cell. 2003 Aug 22;114(4):469-82
12941275
Exp Mol Pathol. 2007 Feb;82(1):25-32
17081516
Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1625-32
8675406