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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:p>\n                    Merkel cell polyomavirus (MCV or MCPyV) is an alphapolyomavirus causing human Merkel cell carcinoma and encodes four tumor (T) antigen proteins: large T (LT), small tumor (sT), 57 kT, and middle T (MT)\/alternate LT open reading frame proteins. We show that MCV MT is generated as multiple isoforms through internal methionine translational initiation that insert into membrane lipid rafts. The membrane-localized MCV MT oligomerizes and promiscuously binds to lipid raft-associated Src family kinases (SFKs). MCV MT-SFK interaction is mediated by a Src homology (SH) 3 recognition motif as determined by surface plasmon resonance, coimmunoprecipitation, and bimolecular fluorescence complementation assays. SFK recruitment by MT leads to tyrosine phosphorylation at a SH2 recognition motif (pMT\n                    <jats:sup>Y114<\/jats:sup>\n                    ), allowing interaction with phospholipase C gamma 1 (PLC\u03b31). The secondary recruitment of PLC\u03b31 to the SFK-MT membrane complex promotes PLC\u03b31 tyrosine phosphorylation on Y783 and activates the NF-\u03baB inflammatory signaling pathway. Mutations at either the MCV MT SH2 or SH3 recognition sites abrogate PLC\u03b31-dependent activation of NF-\u03baB signaling and increase viral replication after MCV genome transfection into 293 cells. These findings reveal a conserved viral targeting of the SFK-PLC\u03b31 pathway by both MCV and murine polyomavirus (MuPyV) MT proteins. The molecular steps in how SFK-PLC\u03b31 activation is achieved, however, differ between these two viruses.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2316467120","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T15:11:26Z","timestamp":1702307486000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":14,"title":["Membrane-bound Merkel cell polyomavirus middle T protein constitutively activates PLC\u03b31 signaling through Src-family kinases"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3613-4070","authenticated-orcid":false,"given":"Wen-Yu","family":"Peng","sequence":"first","affiliation":[{"name":"School of Medicine, Tsinghua University, Beijing 100084, China"},{"name":"Cancer Virology Program, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 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