title: Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC delta and E-cadherin.
abstract: 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.
authors: Department of Medicine, University of Chicago, Chicago, IL 60637, USA. yzhao@medicine.bsd.uchicago.edu
authors: Yutong
authors: Y
authors: Zhao
authors: Donghong
authors: D
authors: He
authors: Randi
authors: R
authors: Stern
authors: Peter V
authors: PV
authors: Usatyuk
authors: Ernst Wm
authors: EW
authors: Spannhake
authors: Ravi
authors: R
authors: Salgia
authors: Viswanathan
authors: V
authors: Natarajan
mesh_terms: 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*
chemical_list: 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
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