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The targets of RhoBTB1 in placenta have not been identified. Using RNAscope, we show that RhoBTB1 is mainly expressed in syncytiotrophoblasts (SCT) in the human and mouse placenta. We employed ascorbate peroxidase 2\u2010mediated targeted proteomics to identify RhoBTB1 binding proteins in immortalized human extravillous trophoblast (HTR8\/SVneo) cells. We selected 9 RhoBTB1\u2010interacting proteins to examine functionally. Two of these, S\u2010Phase Kinase Associated Protein 2 (SKP2) and Rho GTPase\u2010Activating Protein 29 (ArhGAP29), increased in abundance when Cullin activity was blocked by the neddylation inhibitor MLN4924 and co\u2010immunoprecipitated with RhoBTB1. SKP2 increased in abundance in CRISPR\u2010Cas9 HEK293 cells that lack CUL3, and in HTR8\/SVneo cells after siRNA\u2010mediated inhibition of RhoBTB1. SKP2 was ubiquitinated by a RhoBTB1\u2010 and CUL3\u2010dependent mechanism providing evidence that its stability is regulated by RhoBTB1\/CUL3. Like RhoBTB1, SKP2 is highly expressed in the placenta. Reanalysis of single cell RNA sequencing data sets revealed that SKP2 exhibits co\u2010expression with RhoBTB1 in SCT precursor cells, SCTs, and cytotrophoblasts. These findings identify SKP2 as a RhoBTB1\/CUL3 target in the placenta.<\/jats:p>","DOI":"10.14814\/phy2.71039","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:21:54Z","timestamp":1785903714000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evidence that S\u2010phase kinase associated protein 2 (\n                    <scp>SKP2<\/scp>\n                    ) is ubiquitinated and degraded via a Rho\u2010related\n                    <scp>BTB<\/scp>\n                    domain containing 1 (\n                    <scp>RhoBTB1<\/scp>\n                    ) and Cullin\u20103 mechanism in placenta"],"prefix":"10.14814","volume":"14","author":[{"given":"Alina L.","family":"Tvina","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Christine","family":"Livergood","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie W.","family":"Hole","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan A.","family":"Opichka","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisangeli Muniz","family":"Irizarry","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko\u2010Ting","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey K.","family":"Wackman","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin L.","family":"Grobe","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1887-7367","authenticated-orcid":false,"given":"Pablo","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"McIntosh","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1453-0921","authenticated-orcid":false,"given":"Curt D.","family":"Sigmund","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.129793"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.02.529"},{"key":"e_1_2_10_4_1","first-page":"403","article-title":"Preeclampsia: Long\u2010term consequences for vascular health","volume":"11","author":"Amaral L. 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