GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325970/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325970GEOGSEfalseGlypican-1 upregulation elicited in response to a cell-impermeable kinase inhibitor and its overexpression enhance HIV infectionStudies of herpes simplex virus (HSV) entry revealed a previously unrecognized "outside-in" signaling pathway involving phosphatidylserine (PS) scrambling and associated translocation and subsequent extracellular activation of canonical intracellular proteins, including Akt. We hypothesized that HIV-1, which activates a different scramblase, TMEM16F, to induce PS externalization, may similarly trigger an "outside-in" signaling response to promote viral entry. To study this process, we utilized a cell-impermeable staurosporine analog, alkyl-CIMSS, which is a broadly active kinase inhibitor that blocks HSV-induced exofacial Akt phosphorylation, and HSV entry. We show that TMEM16F-mediated PS externalization in response to HIV is not associated with Akt translocation; however, surprisingly, pretreatment of cells with alkyl-CIMSS enhanced HIV-1 infection post-entry. To identify potential biological processes that mediated this enhancement, we performed whole-cell total and phosphoproteomics, and bulk RNA sequencing. Cells treated with alkyl-CIMSS exhibited increased cyclin-dependent kinase (CDK) activity, resulting in higher levels of phosphorylated SAMHD1. Further, alkyl-CIMSS treatment robustly upregulated the cell surface density of the proteoglycan glypican-1 (GPC1). Lentivirus-driven GPC1 overexpression or shRNA knockdown demonstrated that, independent of alkyl-CIMSS treatment, GPC1 expression promotes HIV infection. Collectively, these findings demonstrate that alkyl-CIMSS modulates the exofacial plasma membrane to promote susceptibility to HIV infection by increasing CDK activity and upregulating GPC1.2026/04/01GSE325970GSM9618168GSM9618169GSM9618177GSM9618178GSM9618175GSM9618176GSM9618173GSM9618174GSM9618171GSM9618172GSM961817034281325970Homo sapiens[42112903]