Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration

BackgroundLysophosphatidic acid (LPA) is a bioactive lysophospholipid, which plays a crucial role in cell proliferation, migration, and differentiation. LPA exerts its biological effects mainly through cell-surface LPA receptors (LPA1-6), which belong to the G protein-coupled receptor (GPCR) family. Recent studies suggest that cross-talk between receptor tyrosine kinases (RTKs) and GPCRs modulates GPCR-mediated signaling. TrkA receptor is a RTK, which mediates nerve growth factor (NGF)-induced biological functions including cell migration in neuronal and non-neuronal tissues.Methods and ResultsHere, we show that LPA treatment of the murine lung epithelial cell line (MLE-12 cells) induced tyrosine phosphorylation of TrkA in both time- and dose-dependent manners. These effects were attenuated by downregulating the LPA1 receptor. Furthermore, LPA induces interaction between LPA1 and TrkA. Co-immunoprecipitation experiment reveals that c-terminus of LPA1 contains the binding site for TrkA. Further, we found that LPA1 and phosphorylated TrkA were co-localized in both the plasma membrane and cytoplasm. Pretreatment with a TrkA inhibitor attenuated LPA-induced phosphorylation of TrkA receptor and LPA1 internalization as well as lung epithelial cell migration.ConclusionThese studies reveal a molecular mechanism for the transactivation of TrkA by LPA, and suggest that the cross-talk between LPA1 and TrkA regulates LPA-induced receptor internalization and lung epithelial cell migration.This work was supported by the National Institutes of Health (R01HL091916 and R01HL112791 to Y.Z, R01GM115389 to J.Z.), American Heart Association 12SDG9050005 (J.Z.), American Lung Association Biomedical Research Grant RG350146 (J.Z.).

Download Full-text

Autotaxin induces lung epithelial cell migration through lysoPLD activity-dependent and -independent pathways

Biochemical Journal ◽

10.1042/bj20110274 ◽

2011 ◽

Vol 439 (1) ◽

pp. 45-55 ◽

Cited By ~ 28

Author(s):

Jing Zhao ◽

Donghong He ◽

Evgeny Berdyshev ◽

Mintao Zhong ◽

Ravi Salgia ◽

...

Keyword(s):

Cell Migration ◽

Epithelial Cell ◽

Cell Surface ◽

Leading Edge ◽

Lung Epithelial Cell ◽

Intratracheal Administration ◽

Lpa Receptor ◽

Epithelial Cell Migration ◽

Lung Epithelial ◽

Integrin Β4

Lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodelling and repair after lung injury. In the present paper we hypothesize that secreted ATX (autotaxin), which exhibits lysoPLD (lysophospholipase D) activity, stimulates lung epithelial cell migration through LPA (lysophosphatidic acid) generation-dependent and -independent pathways. Release of endogenous ATX protein and activity was detected in lung epithelial cell culture medium. ATX with V5 tag overexpressed conditional medium had higher LPA levels compared with control medium and stimulated cell migration through Gαi-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKC (protein kinase C) δ and cortactin at the leading edge of migrating cells. Inhibition of PKCδ attenuated ATX–V5 overexpressed conditional medium-mediated phosphorylation of cortactin. In addition, a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induced lung epithelial cell migration. Extracelluar ATX bound to the LPA receptor and integrin β4 complex on A549 cell surface. Finally, intratracheal administration of LPS (lipopolysaccharide) into the mouse airway induced ATX release and LPA production in BAL (bronchoalveolar lavage) fluid. These results suggested a significant role for ATX in lung epithelial cell migration and remodelling through its ability to induce LPA production-mediated phosphorylation of PKCδ and cortactin. In addition we also demonstrated assocation of ATX with the epithelial cell-surface LPA receptor and integrin β4.

Download Full-text

Oxidative stress destabilizes protein arginine methyltransferase 4 via glycogen synthase kinase 3β to impede lung epithelial cell migration

AJP Cell Physiology ◽

10.1152/ajpcell.00073.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. C285-C294 ◽

Cited By ~ 4

Author(s):

Xiuying Li ◽

Yandong Lai ◽

Jin Li ◽

Mingyi Zou ◽

Chunbin Zou

Keyword(s):

Oxidative Stress ◽

Cell Migration ◽

Epithelial Cell ◽

Glycogen Synthase ◽

Lung Epithelial Cell ◽

Glycogen Synthase Kinase 3Β ◽

Arginine Methyltransferase ◽

Epithelial Cell Migration ◽

Lung Epithelial ◽

Gsk 3Β

Oxidative stress impacts normal cellular function leading to the pathogenesis of various diseases including pulmonary illnesses. Protein arginine methyltransferase 4 (PRMT4) is critical for normal lung alveolar epithelial cell development; however, the regulation of PRMT4 within such pulmonary diseases has yet to be elucidated. Using biochemical approaches, we uncovered that peroxide (H2O2) treatment decreases PRMT4 protein stability in murine lung epithelial (MLE12) cells to impede cell migration. Protein kinase glycogen synthase kinase 3β (GSK-3β) interacts with PRMT4 and catalyzes PRMT4 T132 phosphorylation that protects PRMT4 from ubiquitin proteasomal degradation. H2O2 downregulates GSK-3β to reduce PRMT4 at protein level. PRMT4 promotes cell migration and H2O2 degrades PRMT4 to inhibit lung epithelial cell migration. These observations demonstrate that oxidative stress destabilizes PRMT4 via GSK-3β signaling to impede lung epithelial cell migration that may hinder the lung repair and regeneration process.

Download Full-text

Activation of protein kinase A accelerates bovine bronchial epithelial cell migration

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00148.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. L1108-L1116 ◽

Cited By ~ 32

Author(s):

John R. Spurzem ◽

Jitendrakumar Gupta ◽

Thomas Veys ◽

Kristen R. Kneifl ◽

Stephen I. Rennard ◽

...

Keyword(s):

Cell Migration ◽

Protein Kinase ◽

Epithelial Cell ◽

Epithelial Cells ◽

Protein Kinase A ◽

Bronchial Epithelial Cell ◽

Bronchial Epithelial Cells ◽

Bronchial Epithelial ◽

Epithelial Cell Migration ◽

Kinase A

Bronchial epithelial cell migration is required for the repair of damaged airway epithelium. We hypothesized that bronchial epithelial cell migration during wound repair is influenced by cAMP and the activity of its cyclic nucleotide-dependent protein kinase, protein kinase A (PKA). We found that, when confluent monolayers of bronchial epithelial cells are wounded, an increase in PKA activity occurs. Augmentation of PKA activity with a cell-permeable analog of cAMP, dibutyryl adenosine 3′,5′-cyclic monophosphate, isoproterenol, or a phosphodiesterase inhibitor accelerated migration of normal bronchial epithelial cells in in vitro wound closure assays and Boyden chamber migration assays. A role for PKA activity was also confirmed with a PKA inhibitor, KT-5720, which reduced stimulated migration. Augmentation of PKA activity reduced the levels of active Rho and the formation of focal adhesions. These studies suggest that PKA activation modulates Rho activity, migration mechanisms, and thus bronchial epithelial repair mechanisms.

Download Full-text