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We identified CTRP8 as a ligand of the G protein\u2010coupled receptor relaxin family peptide receptor 1 (RXFP1) in glioblastoma multiforme (GBM). The CTRP8\u2010RXFP1 ligand\u2013receptor system protects human GBM cells against the DNA\u2010alkylating damage\u2010inducing temozolomide (TMZ), the drug of choice for the treatment of patients with GBM. The DNA protective role of CTRP8 was dependent on a functional RXFP1\u2010STAT3 signaling cascade and targeted the monofunctional glycosylase\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylpurine DNA glycosylase (MPG) for more efficient base excision repair of TMZ\u2010induced DNA\u2010damaged sites. CTRP8 also improved the survival of GBM cells by upregulating anti\u2010apoptotic BCl\u20102 and BCL\u2010XL. Here, we have identified Janus\u2010activated kinase 3 (JAK3) as a novel member of a novel CTRP8\u2010RXFP1\u2010JAK3\u2010STAT3 signaling cascade that caused an increase in cellular protein content and activity of the small Rho GTPase Cdc42. This is associated with significant F\u2010actin remodeling and increased GBM motility. Cdc42 was critically important for the upregulation of the actin nucleation complex N\u2010Wiskott\u2013Aldrich syndrome protein\/Arp3\/4 and actin elongation factor profilin\u20101. The activation of the RXFP1\u2010JAK3\u2010STAT3\u2010Cdc42 axis by both RXFP1 agonists, CTRP8 and relaxin\u20102, caused extensive filopodia formation. This coincided with enhanced activity of ezrin, a key factor in tethering F\u2010actin to the plasma membrane, and inhibition of the actin filament severing activity of cofilin. The F\u2010actin remodeling and pro\u2010migratory activities promoted by the novel RXFP1\u2010JAK3\u2010STAT3\u2010Cdc42 axis were blocked by JAK3 inhibitor tofacitinib and STAT3 inhibitor STAT3 inhibitor VI. This provides a new rationale for the design of JAK3 and STAT3 inhibitors with better brain permeability for clinical treatment of the pervasive brain invasiveness of GBM.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.12981","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T13:45:29Z","timestamp":1620481529000},"page":"368-387","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Novel CTRP8\u2010RXFP1\u2010JAK3\u2010STAT3 axis promotes Cdc42\u2010dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells"],"prefix":"10.1002","volume":"16","author":[{"given":"Aleksandra","family":"Glogowska","sequence":"first","affiliation":[{"name":"Department of Human Anatomy and Cell Science Rady Faculty of Health Sciences College of Medicine University of Manitoba Winnipeg 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