Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC delta and E-cadherin.
Previously we demonstrated that ligation of lysophosphatidic acid (LPA) to G protein-coupled LPA receptors induces transactivation of receptor tyrosine kinases (RTKs), such as platelet-derived growth factor receptor beta (PDGF-Rbeta) and epidermal growth factor receptor (EGF-R), in primary cultures of human bronchial epithelial cells (HBEpCs). Here we examined the role of LPA on c-Met redistribution and modulation of hepatocyte growth factor (HGF)/c-Met pathways in HBEpCs. Treatment of HBEpCs with LPA-induced c-Met serine phosphorylation and redistribution to plasma membrane, while treatment with HGF-induced c-Met internalization. Pretreatment with LPA reversed HGF-induced c-Met internalization. Overexpression of dominant negative (Dn)-PKC delta or pretreatment with Rottlerin or Pertussis toxin (PTx) attenuated LPA-induced c-Met serine phosphorylation and redistribution. Co-immnuoprecipitation and immunocytochemistry showed that E-cadherin interacted with c-Met in HBEpCs. LPA treatment induced E-cadherin and c-Met complex redistribution to plasma membranes. Overexpression of Dn-PKC delta attenuated LPA-induced E-cadherin redistribution and E-cadherin siRNA attenuated LPA-induced c-Met redistribution to plasma membrane. Furthermore, pretreatment of LPA attenuated HGF-induced c-Met tyrosine phosphorylation and downstream signaling, such as Akt kinase phosphorylation and cell motility. These results demonstrate that LPA regulates c-Met function through PKC delta and E-cadherin in HBEpCs, suggesting an alternate function of the cross-talk between G-protein-coupled receptors (GPCRs) and RTKs in HBEpCs.
Zhao
Yutong
Y
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. yzhao@medicine.bsd.uchicago.edu
He
Donghong
D
Stern
Randi
R
Usatyuk
Peter V
PV
Spannhake
Ernst Wm
EW
Salgia
Ravi
R
Natarajan
Viswanathan
V
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008954:Models, Biological; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000098:Acetophenones; D001578:Benzopyrans; D015820:Cadherins; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D010768:Phosphoserine; D019000:Phosphotyrosine; D017228:Hepatocyte Growth Factor; C085746:rottlerin; D019859:Proto-Oncogene Proteins c-met; D051745:Protein Kinase C-delta; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C032881:lysophosphatidic acid
Neurochem Res. 2002 Aug;27(7-8):619-27
12374197
J Biol Chem. 2004 Sep 24;279(39):41085-94
15280372
Mol Biol Cell. 2003 Apr;14(4):1346-54
12686592
Mol Cell Biochem. 2005 Aug;276(1-2):149-57
16132696
Clin Cancer Res. 2002 Feb;8(2):620-7
11839685
Cancer Res. 2006 Dec 1;66(23):11094-6
17145849
Oncogene. 2001 May 17;20(22):2761-70
11420688
J Cell Biol. 1994 Dec;127(6 Pt 2):1783-7
7806559
J Environ Pathol Toxicol Oncol. 2003;22(3):147-65
14529091
Biochem Biophys Res Commun. 2001 Mar 30;282(2):575-9
11401499
Methods Mol Biol. 2006;332:51-77
16878685
Biochem Biophys Res Commun. 1999 Aug 2;261(2):406-11
10425198
Traffic. 2001 Jan;2(1):12-8
11208164
Cancer Lett. 2005 Jul 8;225(1):1-26
15922853
J Biol Chem. 1991 May 5;266(13):8363-8
2022652
J Biol Chem. 2007 Apr 6;282(14):10172-9
17287216
Int J Mol Med. 2001 Apr;7(4):385-8
11254878
Curr Pharm Des. 2004;10(28):3539-45
15579051
J Biol Chem. 2007 Feb 23;282(8):5814-24
17172642
Curr Med Chem. 2000 Sep;7(9):911-43
10911023
J Invest Dermatol. 1995 Jul;105(1 Suppl):14S-19S
7615991
J Biol Chem. 2006 Jul 14;281(28):19501-11
16687414
EMBO J. 2004 Oct 1;23(19):3721-34
15385963
J Cell Sci. 2001 Mar;114(Pt 6):1213-20
11228164
Breast Cancer Res. 2007;9(1):R8
17244359
Biochim Biophys Acta. 1993 Dec 23;1155(3):357-71
8268192
J Biol Chem. 1991 Aug 25;266(24):16098-104
1651934
Science. 2001 Nov 30;294(5548):1875-8
11729304
FEBS Lett. 2004 Nov 19;577(3):333-8
15556605
Biochemistry. 2006 May 23;45(20):6241-51
16700535
World J Gastroenterol. 2005 Sep 28;11(36):5638-43
16237757
Ann N Y Acad Sci. 2006 Nov;1088:297-306
17192575
Cancer Res. 2003 Oct 1;63(19):6272-81
14559814
Biochem J. 2005 Jan 15;385(Pt 2):493-502
15461590
J Biol Chem. 2003 Oct 10;278(41):39931-40
12890682
Adv Enzyme Regul. 2007;47:271-80
17337042
FEBS Lett. 2003 Apr 10;540(1-3):106-10
12681492
EMBO J. 2004 Apr 21;23(8):1739-48
15057284
Curr Opin Cell Biol. 1999 Apr;11(2):177-83
10209148
Biochem Biophys Res Commun. 2006 Oct 27;349(3):976-86
16970908
J Biol Chem. 2004 Jun 18;279(25):26445-52
15075332
Clin Cancer Res. 2005 Mar 15;11(6):2312-9
15788682
J Biol Chem. 1990 Jun 25;265(18):10226-31
2354998
Biochem J. 2006 Feb 1;393(Pt 3):657-68
16197369
Cancer Res. 2006 Apr 1;66(7):3603-10
16585185
Oncogene. 1999 Nov 18;18(48):6776-84
10597286
J Biol Chem. 2004 Jul 9;279(28):28989-97
15123706
Biochim Biophys Acta. 2002 May 23;1582(1-3):70-1
12069811
Mol Interv. 2007 Feb;7(1):17-25
17339603
FEBS Lett. 1993 Aug 23;329(1-2):147-52
8394828