{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:08:54Z","timestamp":1790352534961,"version":"4.1.0"},"reference-count":92,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NIAMS","award":["AR066044"],"award-info":[{"award-number":["AR066044"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tumor necrosis factor-alpha (TNF-\u03b1) signaling regulates phosphorylation of L-plastin, which is involved in forming the nascent sealing zone, a precursor zone for the matured sealing ring. This study aimed to illustrate the molecular mechanisms of L-plastin phosphorylation and the subsequent formation of the nascent sealing zone in osteoclasts treated with TNF-\u03b1. Here, we report that anti-TNF-receptor 1, inhibitors of signaling proteins (Src, PI3-K, Rho, and Rho-kinase), and siRNA of TRAF-6 attenuated the phosphorylation of LPL and filamentous actin content significantly in the presence of TNF-\u03b1. An inhibitor of integrin \u03b1v\u03b23, PKC, or PKA did not inhibit TNF-\u03b1-induced L-plastin phosphorylation. Inhibitors of Src and PI3-K and not Rho or Rho-kinase reduced tyrosine phosphorylation of TRAF-6, suggesting that Src and PI3-K regulate TRAF-6 phosphorylation, and Rho and Rho-kinase are downstream of TRAF-6 regulation. Osteoclasts expressing constitutively active or kinase-defective Src proteins were used to determine the role of Src on L-plastin phosphorylation; similarly, the effect of Rho was confirmed by transducing TAT-fused constitutively active (V14) or dominant-negative (N19) Rho proteins into osteoclasts. Pull-down analysis with glutathione S-transferase-fused SH2 and SH3 domains of Src and PI3-K demonstrated coprecipitation of L-plastin and TRAF-6 with the SH3 and SH2 domains of the PI3-K and Src proteins. However, the actual order of the interaction of proteins requires further elucidation; a comprehensive screening should corroborate the initial findings of protein interactions via the SH2\/SH3 domains. Ultimately, inhibition of the interaction of proteins with SH2\/SH3 could reduce L-plastin phosphorylation and affect NSZ formation and bone resorption in conditions that display osteoclast activation and bone loss.<\/jats:p>","DOI":"10.3390\/cells10092432","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T12:00:44Z","timestamp":1631707244000},"page":"2432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["L-Plastin Phosphorylation: Possible Regulation by a TNFR1 Signaling Cascade in Osteoclasts"],"prefix":"10.3390","volume":"10","author":[{"given":"Meenakshi A.","family":"Chellaiah","sequence":"first","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/(SICI)1097-0169(1997)37:4<308::AID-CM3>3.0.CO;2-0","article-title":"Fimbrin in podosomes of monocyte-derived osteoclasts","volume":"37","author":"Babb","year":"1997","journal-title":"Cell Motil. 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