{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:41:46Z","timestamp":1791412906787,"version":"4.3.3"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"22","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["K01 CA197138"],"award-info":[{"award-number":["K01 CA197138"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R35 CA197709"],"award-info":[{"award-number":["R35 CA197709"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:p>\n                    Neurofibromin, the protein product of the neurofibromatosis type 1 (\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    ) gene, requires the direct binding interaction with SPRED to negatively regulate the RAS-MAPK pathway. Although the region of neurofibromin that stimulates the intrinsic GTPase activity of RAS represents only a small percentage of the entire protein, a large degree of the\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    structural domains and their correlating mechanistic functions remain elusive. Here, we demonstrate RAS-independent biochemical and signaling functions regulated by the coordinate control of NF1 and SPRED1\/2. Utilizing CRISPR-Cas9 methods to ablate\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">SPRED1\/2<\/jats:italic>\n                    in isogenic \u201cRASless\u201d mouse embryonic fibroblast (MEF) cell lines expressing either the KRAS4b wild-type variant or an oncogenic\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    -mutation, we show loss of SPRED1\/2 phenocopies NF1 loss and their cooperation is required to modulate MAPK-AKT signaling. Moreover, NF1 or SPRED1\/2 loss also resulted in a potent suppression of the RAS family GTPases, RRAS and RRAS2, occurring independently of RAS or AKT pathway activation. A transcriptome microarray analysis of the NF1 or SPRED1\/2 knockout MEF cells revealed a specific subset of RAS-independent, NF1\u2013SPRED1\/2-dependent gene signatures, in which these same genes were also directly regulated by the RAS-GTPase function of neurofibromin. The modulation of these NF1\u2013SPRED1\/2-dependent downstream signaling effectors were further corroborated in Schwann cell models derived from Neurofibromatosis type I patients that consisted of either plexiform neurofibroma cells or unaffected nerve cells abrogated of NF1 or neurofibromin RAS-GAP activity. Taken together, this study provides RAS-independent functions that are dependent on the cooperation of NF1 and SPRED1\/2 in a manner that is uncoupled from canonical MAPK signaling.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2535319123","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:47:15Z","timestamp":1779904035000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["NF1 and SPRED1\/2 cooperate through RAS-MAPK-independent functions"],"prefix":"10.1073","volume":"123","author":[{"given":"Jillian M.","family":"Silva","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizzeth","family":"Canche","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Cheng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2703-2347","authenticated-orcid":false,"given":"Lucy C.","family":"Young","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6619-7120","authenticated-orcid":false,"given":"Frank","family":"McCormick","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(92)90270-N"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1993.00540110065007"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(91)90017-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90151-4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90150-D"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90149-9"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000981200"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng2113"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.190876.112"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198112313052704"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2007-3204"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2009.09.042"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-52902-2.00053-9"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)00259-6"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/35088082"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90014-7"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/356713a0"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90407-4"},{"key":"e_1_3_4_19_2","first-page":"507","article-title":"Ras-GTP levels are elevated in human NF1 peripheral nerve tumors","volume":"12","author":"Guha A.","year":"1996","unstructured":"A. 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