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• W2473674911 abstract "We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser127 and Ser397. Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser127 and Ser397 via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser127, and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway. We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser127 and Ser397. Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser127 and Ser397 via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser127, and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway. The proliferation of the epithelial cells of the intestinal mucosa is a tightly regulated process modulated by a broad range of regulatory peptides, neurotransmitters, bioactive lipids, and differentiation signals (1Crosnier C. Stamataki D. Lewis J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.Nat. Rev. Genet. 2006; 7: 349-359Crossref PubMed Scopus (567) Google Scholar). Many of these stimuli initiate their characteristic effects in their target cells through G protein-coupled receptors (GPCRs) 2The abbreviations used are:GPCRG protein-coupled receptorYAPYes-associated proteinANG IIangiotensin IIqPCRquantitative PCRLMBleptomycin BNESnuclear export sequenceAT1ANG II type 1TRITCtetramethylrhodamine isothiocyanate. 2Rozengurt E. Walsh J.H. Gastrin, CCK, signaling, and cancer.Annu. Rev. Physiol. 2001; 63: 49-76Crossref PubMed Scopus (181) Google Scholar, 3Rozengurt E. Mitogenic signaling pathways induced by G protein-coupled receptors.J. Cell Physiol. 2007; 213: 589-602Crossref PubMed Scopus (387) Google Scholar, 4Raufman J.-P. Samimi R. Shah N. Khurana S. Shant J. Drachenberg C. Xie G. Wess J. Cheng K. Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia.Cancer Res. 2008; 68: 3573-3578Crossref PubMed Scopus (80) Google Scholar, 5Rey O. Chang W. Bikle D. Rozengurt N. Young S.H. Rozengurt E. Negative cross-talk between calcium-sensing receptor and β-catenin signaling systems in colonic epithelium.J. Biol. Chem. 2012; 287: 1158-1167Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 6Lee S.J. Leoni G. Neumann P.A. Chun J. Nusrat A. Yun C.C. Distinct phospholipase C-β isozymes mediate lysophosphatidic acid receptor 1 effects on intestinal epithelial homeostasis and wound closure.Mol. Cell. Biol. 2013; 33: 2016-2028Crossref PubMed Scopus (40) Google Scholar. Despite their fundamental importance for understanding intestinal homeostasis, wound healing, and pathogenesis of human diseases, the intracellular signal transduction mechanisms that mediate GPCR-induced proliferation of intestinal epithelial cells remain incompletely understood. G protein-coupled receptor Yes-associated protein angiotensin II quantitative PCR leptomycin B nuclear export sequence ANG II type 1 tetramethylrhodamine isothiocyanate. The highly conserved Hippo pathway, originally identified in Drosophila, is attracting intense interest as a key regulator of organ size, tissue regeneration, tumorigenesis, and GPCR signaling (7Yu F.-X. Guan K.-L. The Hippo pathway: regulators and regulations.Genes. Dev. 2013; 27: 355-371Crossref PubMed Scopus (871) Google Scholar). Canonical Hippo signals in vertebrate cells are transduced through a core serine/threonine kinase cascade wherein Mst1/2 kinases, in complex with the scaffold Sav1, phosphorylate and activate Lats1/2 (large tumor suppressor 1//2), in complex with its regulatory protein MOB1/2 (8Avruch J. Zhou D. Fitamant J. Bardeesy N. Mou F. Barrufet L.R. Protein kinases of the Hippo pathway: regulation and substrates.Semin. Cell Dev. Biol. 2012; 23: 770-784Crossref PubMed Scopus (166) Google Scholar). In addition to Mst1/2, Hppy/MAP4Ks were recently identified as alternative kinases that phosphorylate Lats1/2 (9Zheng Y. Wang W. Liu B. Deng H. Uster E. Pan D. Identification of happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the hippo kinase cascade.Dev. Cell. 2015; 34: 642-655Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 10Meng Z. Moroishi T. Mottier-Pavie V. Plouffe S.W. Hansen C.G. Hong A.W. Park H.W. Mo J.-S. Lu W. Lu S. Flores F. Yu F.-X. Halder G. Guan K.-L. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.Nat. Commun. 2015; 6: 8357Crossref PubMed Scopus (299) Google Scholar). In turn, Lats1/2 phosphorylates the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ), two major downstream effectors of the Hippo pathway. The intracellular distribution of YAP and TAZ is highly dynamic, exhibiting rapid nuclear-cytoplasmic shuttling. The phosphorylation of YAP and TAZ by Lats1/2 is widely thought to restrict their activity, cellular localization, and stability. In the absence of phosphorylation, YAP localizes to the nucleus where it binds and activates the TEA domain DNA-binding transcription factors thereby stimulating the expression of proliferative and anti-apoptotic genes. Several studies indicate that YAP acts as a context-specific oncogene (11Moroishi T. Hansen C.G. Guan K.-L. The emerging roles of YAP and TAZ in cancer.Nat. Rev. Cancer. 2015; 15: 73-79Crossref PubMed Scopus (790) Google Scholar) and that the Hippo pathway inhibits its activity. Despite intense interest in this novel pathway, many important questions relating to its function remain unanswered as follows: 1) the mechanism(s) by which upstream signals feed into the Hippo cascade remain incompletely defined; 2) YAP not only acts as a transcriptional co-activator in the nucleus but also mediates biological functions in other cellular locations, including the cytoplasm (12Chen C.-L. Tsukamoto H. Liu J.-C. Kashiwabara C. Feldman D. Sher L. Dooley S. French S.W. Mishra L. Petrovic L. Jeong J.H. Machida K. Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells.J. Clin. Invest. 2013; 123: 2832-2849Crossref PubMed Scopus (124) Google Scholar, 13Shanzer M. Ricardo-Lax I. Keshet R. Reuven N. Shaul Y. The polyomavirus middle T-antigen oncogene activates the Hippo pathway tumor suppressor Lats in a Src-dependent manner.Oncogene. 2015; 34: 4190-4198Crossref PubMed Scopus (16) Google Scholar); and 3) YAP cross-talks with other important signaling pathways, but the biological outcome (positive or negative) of these interactions remains unclear and is likely cell context-dependent. Even at the most fundamental level, the precise role of YAP in intestinal epithelial cell proliferation remains incompletely understood, as evidence for both growth-stimulatory and growth-suppressive roles of YAP/TAZ has been presented 14Barry E.R. Morikawa T. Butler B.L. Shrestha K. de la Rosa R. Yan K.S. Fuchs C.S. Magness S.T. Smits R. Ogino S. Kuo C.J. Camargo F.D. Restriction of intestinal stem cell expansion and the regenerative response by YAP.Nature. 2013; 493: 106-110Crossref PubMed Scopus (399) Google Scholar, 15Lee K.-W. Lee S.S. Kim S.-B. Sohn B.H. Lee H.-S. Jang H.-J. Park Y.-Y. Kopetz S. Kim S.S. Oh S.C. Lee J.-S. Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients.Clin. Cancer Res. 2015; 21: 357-364Crossref PubMed Scopus (108) Google Scholar, 16Imajo M. Ebisuya M. Nishida E. Dual role of YAP and TAZ in renewal of the intestinal epithelium.Nat Cell Biol. 2015; 17: 7-19Crossref PubMed Scopus (133) Google Scholar, 17Hong A.W. Meng Z. Guan K.-L. The Hippo pathway in intestinal regeneration and disease.Nat. Rev. Gastroenterol. Hepatol. 2016; 13: 324-337Crossref PubMed Scopus (162) Google Scholar. GPCR agonists act as important signals upstream of the Hippo/YAP/TAZ pathway. Protein kinase D (PKD), a protein kinase family within the Ca2+/calmodulin-dependent kinase group (18Rozengurt E. Rey O. Waldron R.T. Protein kinase D signaling.J. Biol. Chem. 2005; 280: 13205-13208Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar), has emerged as a prominent downstream signal induced by GPCRs that function through Gαq/11, Gα12, Gαi, and Rho (18Rozengurt E. Rey O. Waldron R.T. Protein kinase D signaling.J. Biol. Chem. 2005; 280: 13205-13208Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 19Rozengurt E. Protein kinase D signaling: multiple biological functions in health and disease.Physiology. 2011; 26: 23-33Crossref PubMed Scopus (186) Google Scholar, 20Yuan J. Slice L. Walsh J.H. Rozengurt E. Activation of protein kinase D by signaling through the α subunit of the heterotrimeric G protein Gq.J. Biol. Chem. 2000; 275: 2157-2164Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 21Yuan J. Slice L.W. Rozengurt E. Activation of protein kinase D by signaling through Rho and the α subunit of the heterotrimeric G protein G13.J. Biol. Chem. 2001; 276: 38619-38627Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 22Paolucci L. Sinnett-Smith J. Rozengurt E. Lysophosphatidic acid rapidly induces protein kinase D activation through a pertussis toxin-sensitive pathway.Am. J. Physiol. Cell Physiol. 2000; 278: C33-C39Crossref PubMed Google Scholar, 23Chiu T. Rozengurt E. PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC.Am. J. Physiol. Cell Physiol. 2001; 280: C929-C942Crossref PubMed Google Scholar, 24Yuan J. Slice L.W. Gu J. Rozengurt E. Cooperation of Gq, Gi, and G12/13 in protein kinase D activation and phosphorylation induced by lysophosphatidic acid.J. Biol. Chem. 2003; 278: 4882-4891Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 25Yuan J. Rey O. Rozengurt E. Activation of protein kinase D3 by signaling through Rac and the α subunits of the heterotrimeric G proteins G12 and G13.Cell. Signal. 2006; 18: 1051-1062Crossref PubMed Scopus (27) Google Scholar, 26Waldron R.T. Innamorati G. Torres-Marquez M.E. Sinnett-Smith J. Rozengurt E. Differential PKC-dependent and -independent PKD activation by G protein α subunits of the Gq family: selective stimulation of PKD Ser748 autophosphorylation by Gαq.Cell. Signal. 2012; 24: 914-921Crossref PubMed Scopus (20) Google Scholar). PKD1, the founding and most studied member of the PKD family (27Valverde A.M. Sinnett-Smith J. Van Lint J. Rozengurt E. Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 8572-8576Crossref PubMed Scopus (359) Google Scholar, 28Johannes F.J. Prestle J. Eis S. Oberhagemann P. Pfizenmaier K. PKCu is a novel, atypical member of the protein kinase C family.J. Biol. Chem. 1994; 269: 6140-6148Abstract Full Text PDF PubMed Google Scholar), which is composed of PKD1, PKD2, and PKD3, is rapidly activated through protein kinase C (PKC)-mediated phosphorylation of Ser744 and Ser748 in the PKD1 activation loop 29Iglesias T. Waldron R.T. Rozengurt E. Identification of in vivo phosphorylation sites required for protein kinase D activation.J. Biol. Chem. 1998; 273: 27662-27667Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 30Waldron R.T. Rey O. Iglesias T. Tugal T. Cantrell D. Rozengurt E. Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo.J. Biol. Chem. 2001; 276: 32606-32615Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 31Waldron R.T. Rozengurt E. Protein kinase C phosphorylates protein kinase D activation loop Ser744 and Ser748 and releases autoinhibition by the pleckstrin homology domain.J. Biol. Chem. 2003; 278: 154-163Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 32Rey O. Reeve Jr., J.R. Zhukova E. Sinnett-Smith J. Rozengurt E. G protein-coupled receptor-mediated phosphorylation of the activation loop of protein kinase D: dependence on plasma membrane translocation and protein kinase Cϵ.J. Biol. Chem. 2004; 279: 34361-34372Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar. PKD1 catalytic activation within cells leads to its auto-phosphorylation at Ser916 and Ser748 33Matthews S.A. Rozengurt E. Cantrell D. Characterization of serine 916 as an in vivo autophosphorylation site for protein kinase D/protein kinase Cμ.J. Biol. Chem. 1999; 274: 26543-26549Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 34Sinnett-Smith J. Zhukova E. Hsieh N. Jiang X. Rozengurt E. Protein kinase D potentiates DNA synthesis induced by Gq-coupled receptors by increasing the duration of ERK signaling in Swiss 3T3 cells.J. Biol. Chem. 2004; 279: 16883-16893Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 35Sinnett-Smith J. Jacamo R. Kui R. Wang Y.M. Young S.H. Rey O. Waldron R.T. Rozengurt E. Protein kinase D mediates mitogenic signaling by Gq-coupled receptors through protein kinase C-independent regulation of activation Loop Ser744 and Ser748 phosphorylation.J. Biol. Chem. 2009; 284: 13434-13445Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar. Rapid PKC-dependent PKD1 activation is followed by a late PKC-independent phase of activation induced by GPCR agonists (35Sinnett-Smith J. Jacamo R. Kui R. Wang Y.M. Young S.H. Rey O. Waldron R.T. Rozengurt E. Protein kinase D mediates mitogenic signaling by Gq-coupled receptors through protein kinase C-independent regulation of activation Loop Ser744 and Ser748 phosphorylation.J. Biol. Chem. 2009; 284: 13434-13445Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 37Jacamo R. Sinnett-Smith J. Rey O. Waldron R.T. Rozengurt E. Sequential protein kinase C (PKC)-dependent and PKC-independent protein kinase D catalytic activation via Gq-coupled receptors: differential regulation of activation loop Ser(744) and Ser(748) phosphorylation.J. Biol. Chem. 2008; 283: 12877-12887Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Accumulating evidence demonstrates that the PKD family plays an important role in a variety of cellular processes and activities, including cytoskeletal organization, gene expression, cell migration, and proliferation (19Rozengurt E. Protein kinase D signaling: multiple biological functions in health and disease.Physiology. 2011; 26: 23-33Crossref PubMed Scopus (186) Google Scholar). In intestinal epithelial cells, PKD1 activation mediates migration and proliferation both in vitro and in vivo (36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 38Young S.H. Rozengurt N. Sinnett-Smith J. Rozengurt E. Rapid protein kinase D1 signaling promotes migration of intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2012; 303: G356-G366Crossref PubMed Scopus (13) Google Scholar). Accordingly, multiple growth-promoting stimuli rapidly activate PKD1 catalytic activity in intestinal epithelial cells (23Chiu T. Rozengurt E. PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC.Am. J. Physiol. Cell Physiol. 2001; 280: C929-C942Crossref PubMed Google Scholar, 36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 38Young S.H. Rozengurt N. Sinnett-Smith J. Rozengurt E. Rapid protein kinase D1 signaling promotes migration of intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2012; 303: G356-G366Crossref PubMed Scopus (13) Google Scholar, 39Chiu T. Wu S.S. Santiskulvong C. Tangkijvanich P. Yee Jr., H.F. Rozengurt E. Vasopressin-mediated mitogenic signaling in intestinal epithelial cells.Am. J. Physiol. Cell Physiol. 2002; 282: C434-C450Crossref PubMed Scopus (65) Google Scholar, 40Rey O. Zhukova E. Sinnett-Smith J. Rozengurt E. Vasopressin-induced intracellular redistribution of protein kinase D in intestinal epithelial cells.J. Cell Physiol. 2003; 196: 483-492Crossref PubMed Scopus (22) Google Scholar) through activation loop phosphorylation (30Waldron R.T. Rey O. Iglesias T. Tugal T. Cantrell D. Rozengurt E. Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo.J. Biol. Chem. 2001; 276: 32606-32615Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 35Sinnett-Smith J. Jacamo R. Kui R. Wang Y.M. Young S.H. Rey O. Waldron R.T. Rozengurt E. Protein kinase D mediates mitogenic signaling by Gq-coupled receptors through protein kinase C-independent regulation of activation Loop Ser744 and Ser748 phosphorylation.J. Biol. Chem. 2009; 284: 13434-13445Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 37Jacamo R. Sinnett-Smith J. Rey O. Waldron R.T. Rozengurt E. Sequential protein kinase C (PKC)-dependent and PKC-independent protein kinase D catalytic activation via Gq-coupled receptors: differential regulation of activation loop Ser(744) and Ser(748) phosphorylation.J. Biol. Chem. 2008; 283: 12877-12887Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Furthermore, transgenic mice that express elevated PKD1 protein in intestinal epithelial cells display a marked increase in DNA-synthesizing cells in their intestinal crypts and a significant increase in the length and total number of cells per crypt (36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Collectively, these results support the notion that PKD1 signaling is a novel element in the pathway leading to proliferation of intestinal epithelial cells in vitro and in vivo. The mechanisms downstream of PKD1, however, remain to be elucidated, and in particular, cross-talk between PKD and YAP has not been identified either in intestinal epithelial cells or in any other cell type. The results presented here identify a novel temporal pattern of nuclear-cytoplasmic shuttling of endogenous YAP in response to GPCR stimulation in intestinal epithelial cells. Specifically, we show that GPCR activation elicits a rapid but transient YAP phosphorylation and localization to the cytoplasm followed by a second phase involving YAP re-localization to the nucleus and stimulation of YAP/TEAD-regulated genes. Further studies demonstrate, for the first time, cross-talk between PKD and Lats/YAP/TEAD signaling pathways. Based on the results presented here, we conclude that the PKD family controls the localization, phosphorylation, and transcriptional co-activator activity of YAP in intestinal epithelial cells. In turn, YAP is necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. Collectively, our results identify, for the first time, a novel cross-talk between YAP and PKD signaling pathways leading to biphasic regulation of YAP in intestinal epithelial cells. To examine the regulation of YAP cellular localization, phosphorylation, and activity in intestinal epithelial cells, we used the non-transformed IEC-18 and IEC-6 cells (41Quaroni A. Wands J. Trelstad R.L. Isselbacher K.J. Epithelioid cell cultures from rat small intestine. Characterization by morphologic and immunologic criteria.J. Cell Biol. 1979; 80: 248-265Crossref PubMed Scopus (678) Google Scholar, 42Quaroni A. May R.J. Establishment and characterization of intestinal epithelial cell cultures.Methods Cell Biol. 1980; 21B: 403-427Crossref PubMed Scopus (140) Google Scholar), which were derived from neonatal rat small intestine and have characteristics of crypt-type epithelial cells. These cells endogenously express Gαq/11-coupled receptors for angiotensin II (ANG II) and vasopressin (23Chiu T. Rozengurt E. PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC.Am. J. Physiol. Cell Physiol. 2001; 280: C929-C942Crossref PubMed Google Scholar, 39Chiu T. Wu S.S. Santiskulvong C. Tangkijvanich P. Yee Jr., H.F. Rozengurt E. Vasopressin-mediated mitogenic signaling in intestinal epithelial cells.Am. J. Physiol. Cell Physiol. 2002; 282: C434-C450Crossref PubMed Scopus (65) Google Scholar, 40Rey O. Zhukova E. Sinnett-Smith J. Rozengurt E. Vasopressin-induced intracellular redistribution of protein kinase D in intestinal epithelial cells.J. Cell Physiol. 2003; 196: 483-492Crossref PubMed Scopus (22) Google Scholar, 43Wu S.S. Chiu T. Rozengurt E. ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase.Am. J. Physiol. Cell Physiol. 2002; 282: C1432-C1444Crossref PubMed Scopus (42) Google Scholar, 44Chiu T. Santiskulvong C. Rozengurt E. ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 285: G1-G11Crossref PubMed Scopus (41) Google Scholar, 45Chiu T. Santiskulvong C. Rozengurt E. EGF receptor transactivation mediates ANG II-stimulated mitogenesis in intestinal epithelial cells through the PI3-kinase/Akt/mTOR/p70S6K1 signaling pathway.Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 288: G182-G194Crossref PubMed Scopus (70) Google Scholar, 46Young S.H. Rozengurt E. Qdot nanocrystal conjugates conjugated to bombesin or ANG II label the cognate G protein-coupled receptor in living cells.Am. J. Physiol. Cell Physiol. 2006; 290: C728-C732Crossref PubMed Scopus (52) Google Scholar) and have been extensively used as a model system to examine signal transduction pathways in response to GPCR activation (23Chiu T. Rozengurt E. PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC.Am. J. Physiol. Cell Physiol. 2001; 280: C929-C942Crossref PubMed Google Scholar, 36Sinnett-Smith J. Rozengurt N. Kui R. Huang C. Rozengurt E. Protein kinase D1 mediates stimulation of DNA synthesis and proliferation in intestinal epithelial IEC-18 cells and in mouse intestinal crypts.J. Biol. Chem. 2011; 286: 511-520Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 38Young S.H. Rozengurt N. Sinnett-Smith J. Rozengurt E. Rapid protein kinase D1 signaling promotes migration of intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2012; 303: G356-G366Crossref PubMed Scopus (13) Google Scholar, 39Chiu T. Wu S.S. Santiskulvong C. Tangkijvanich P. Yee Jr., H.F. Rozengurt E. Vasopressin-mediated mitogenic signaling in intestinal epithelial cells.Am. J. Physiol. Cell Physiol. 2002; 282: C434-C450Crossref PubMed Scopus (65) Google Scholar, 43Wu S.S. Chiu T. Rozengurt E. ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase.Am. J. Physiol. Cell Physiol. 2002; 282: C1432-C1444Crossref PubMed Scopus (42) Google Scholar, 44Chiu T. Santiskulvong C. Rozengurt E. ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 285: G1-G11Crossref PubMed Scopus (41) Google Scholar, 45Chiu T. Santiskulvong C. Rozengurt E. EGF receptor transactivation mediates ANG II-stimulated mitogenesis in intestinal epithelial cells through the PI3-kinase/Akt/mTOR/p70S6K1 signaling pathway.Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 288: G182-G194Crossref PubMed Scopus (70) Google Scholar, 47Slice L.W. Chiu T. Rozengurt E. Angiotensin II and epidermal growth factor induce cyclooxygenase-2 expression in intestinal epithelial cells through small GTPases using distinct signaling pathways.J. Biol. Chem. 2005; 280: 1582-1593Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). ANG II and vasopressin act as potent growth factors for IEC-18 and IEC-6 cells (23Chiu T. Rozengurt E. PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC.Am. J. Physiol. Cell Physiol. 2001; 280: C929-C942Crossref PubMed Google Scholar, 39Chiu T. Wu S.S. Santiskulvong C. Tangkijvanich P. Yee Jr., H.F. Rozengurt E. Vasopressin-mediated mitogenic signaling in intestinal epithelial cells.Am. J. Physiol. Cell Physiol. 2002; 282: C434-C450Crossref PubMed Scopus (65) Google Scholar, 43Wu S.S. Chiu T. Rozengurt E. ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase.Am. J. Physiol. Cell Physiol. 2002; 282: C1432-C1444Crossref PubMed Scopus (42) Google Scholar, 44Chiu T. Santiskulvong C. Rozengurt E. ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells.Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 285: G1-G11Crossref PubMed Scopus (41) Google Scholar, 45Chiu T. Santiskulvong C. Rozengurt E. EGF receptor transactivation mediates ANG II-stimulated mitogenesis in intestinal epithelial cells through the PI3-kinase/Akt/mTOR/p70S6K1 signaling pathway.Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 288: G182-G194Crossref PubMed Scopus (70) Google Scholar, 47Slice L.W. Chiu T. Rozengurt E. Angiotensin II and epidermal growth factor induce cyclooxygenase-2 expression in intestinal epithelial cells through small GTPases using distinct signaling pathways.J. Biol. Chem. 2005; 280: 1582-1593Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Because the levels of YAP/TAZ influence their association with transcriptional cofactors especially when expressed at elevated levels, we studied the localization, phosphorylation, and activity of the endogenous YAP protein. Initially, we determined the localization of YAP in confluent and quiescent cultures of IEC-18 cells (23Chiu T. Rozengurt E. PKD in intestinal epithelia" @default.
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• W2473674911 creator A5080480389 @default.
• W2473674911 date "2016-08-01" @default.
• W2473674911 modified "2023-10-16" @default.
• W2473674911 title "Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells" @default.
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• W2473674911 doi "https://doi.org/10.1074/jbc.m115.711275" @default.
• W2473674911 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5016186" @default.
• W2473674911 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27369082" @default.
• W2473674911 hasPublicationYear "2016" @default.
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