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dc.contributor.authorLi, Yunpingen_US
dc.contributor.authorReznichenko, Mayaen_US
dc.contributor.authorTribe, Rachel M.en_US
dc.contributor.authorHess, Philip E.en_US
dc.contributor.authorTaggart, Michaelen_US
dc.contributor.authorKim, HakRimen_US
dc.contributor.authorDeGnore, Jon P.en_US
dc.contributor.authorGangopadhyay, Samudraen_US
dc.contributor.authorMorgan, Kathleen G.en_US
dc.date.accessioned2012-01-11T22:26:45Z
dc.date.available2012-01-11T22:26:45Z
dc.date.issued2009-10-16
dc.identifier.citationLi, Yunping, Maya Reznichenko, Rachel M. Tribe, Philip E. Hess, Michael Taggart, HakRim Kim, Jon P. DeGnore, Samudra Gangopadhyay, Kathleen G. Morgan. "Stretch Activates Human Myometrium via ERK, Caldesmon and Focal Adhesion Signaling" PLoS ONE 4(10): e7489. (2009)
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/2144/3295
dc.description.abstractAn incomplete understanding of the molecular mechanisms responsible for myometrial activation from the quiescent pregnant state to the active contractile state during labor has hindered the development of effective therapies for preterm labor. Myometrial stretch has been implicated clinically in the initiation of labor and the etiology of preterm labor, but the molecular mechanisms involved in the human have not been determined. We investigated the mechanisms by which gestation-dependent stretch contributes to myometrial activation, by using human uterine samples from gynecologic hysterectomies and Cesarean sections. Here we demonstrate that the Ca requirement for activation of the contractile filaments in human myometrium increases with caldesmon protein content during gestation and that an increase in caldesmon phosphorylation can reverse this inhibitory effect during labor. By using phosphotyrosine screening and mass spectrometry of stretched human myometrial samples, we identify 3 stretch-activated focal adhesion proteins, FAK, p130Cas, and alpha actinin. FAK-Y397, which signals integrin engagement, is constitutively phosphorylated in term human myometrium whereas FAK-Y925, which signals downstream ERK activation, is phosphorylated during stretch. We have recently identified smooth muscle Archvillin (SmAV) as an ERK regulator. A newly produced SmAV-specific antibody demonstrates gestation-specific increases in SmAV protein levels and stretch-specific increases in SmAV association with focal adhesion proteins. Thus, whereas increases in caldesmon levels suppress human myometrium contractility during pregnancy, stretch-dependent focal adhesion signaling, facilitated by the ERK activator SmAV, can contribute to myometrial activation. These results suggest that focal adhesion proteins may present new targets for drug discovery programs aimed at regulation of uterine contractility.en_US
dc.description.sponsorshipNational Heart, Lung & Blood Institute, National Institute of Child Health & Human Development (HD043054, HL80003, HL86655); Foundation of Anesthesia for Education and Research; Harvard Medical School (Eleanor and Miles Shore Fellowships for Scholars in Medicine); Wellcome Trusten_US
dc.language.isoen
dc.publisherPublic Library of Scienceen_US
dc.rightsLi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.titleStretch Activates Human Myometrium via ERK, Caldesmon and Focal Adhesion Signalingen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pone.0007489
dc.identifier.pmid19834610
dc.identifier.pmcid2759504


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