{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:07:06Z","timestamp":1789927626539,"version":"4.0.1"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS048353"],"award-info":[{"award-number":["R01 NS048353"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS109655"],"award-info":[{"award-number":["R01 NS109655"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["F30 NS063626"],"award-info":[{"award-number":["F30 NS063626"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["F31 NS081824"],"award-info":[{"award-number":["F31 NS081824"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA122804"],"award-info":[{"award-number":["R01 CA122804"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["F30 CA247139"],"award-info":[{"award-number":["F30 CA247139"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["X81XWH-09-1-0086"],"award-info":[{"award-number":["X81XWH-09-1-0086"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-12-1-0164"],"award-info":[{"award-number":["W81XWH-12-1-0164"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Commun Signal"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2\/TC21) subfamily proteins. We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. However, it is unclear whether R-Ras, R-Ras2 and M-Ras are expressed and hyperactivated in MPNSTs and, if so, whether they contribute to MPNST pathogenesis. We assessed the expression and activation of these proteins in MPNST cells and inhibited them to determine the effect this had on proliferation, migration, invasion, survival and the phosphoproteome.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>NF1-associated (ST88-14, 90-8, NMS2, NMS-PC, S462, T265-2c) and sporadic (STS-26T, YST-1) MPNST lines were used. Cells were transfected with doxycycline-inducible vectors expressing either a pan-inhibitor of the R-Ras subfamily [dominant negative (DN) R-Ras] or enhanced green fluorescent protein (eGFP). Methodologies used included immunoblotting, immunocytochemistry, PCR, Transwell migration, <jats:sup>3<\/jats:sup>H-thymidine incorporation, calcein cleavage assays and shRNA knockdowns. Proteins in cells with or without DN R-Ras expression were differentially labeled with SILAC and mass spectrometry was used to identify phosphoproteins and determine their relative quantities in the presence and absence of DN R-Ras. Validation of R-Ras and R-Ras2 action and R-Ras regulated networks was performed using genetic and\/or pharmacologic approaches.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>R-Ras2 was uniformly expressed in MPNST cells, with R-Ras present in a major subset. Both proteins were activated in neurofibromin-null MPNST cells. Consistent with classical Ras inhibition, DN R-Ras and R-Ras2 knockdown inhibited proliferation. However, DN R-Ras inhibition impaired migration and invasion but not survival. Mass spectrometry-based phosphoproteomics identified thirteen protein networks distinctly regulated by DN R-Ras, including multiple networks regulating cellular movement and morphology. ROCK1 was a prominent mediator in these networks. DN R-Ras expression and <jats:italic>RRAS<\/jats:italic> and <jats:italic>RRAS2<\/jats:italic> knockdown inhibited migration and ROCK1 phosphorylation; ROCK1 inhibition similarly impaired migration and invasion, altered cellular morphology and triggered the accumulation of large intracellular vesicles.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>R-Ras proteins function distinctly from classic Ras proteins by regulating distinct signaling pathways that promote MPNST tumorigenesis by mediating migration and invasion.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Plain English Summary<\/jats:title>\n                <jats:p>Mutations of the <jats:italic>NF1<\/jats:italic> gene potentially results in the activation of multiple Ras proteins, which are key regulators of many biologic effects. The protein encoded by the <jats:italic>NF1<\/jats:italic> gene, neurofibromin, acts as an inhibitor of both classic Ras and R-Ras proteins; loss of neurofibromin could cause these Ras proteins to become persistently active, leading to the development of cancer. We have previously shown that three related Ras proteins (the classic Ras proteins) are highly activated in malignant peripheral nerve sheath tumor (MPNST) cells with neurofibromin loss and that they drive cancer cell proliferation and survival by activating multiple cellular signaling pathways. Here, we examined the expression, activation and action of R-Ras proteins in MPNST cells that have lost neurofibromin. Both R-Ras and R-Ras2 are expressed in MPNST cells and activated. Inhibition of R-Ras action inhibited proliferation, migration and invasion but not survival. We examined the activation of cytoplasmic signaling pathways in the presence and absence of R-Ras signaling and found that R-Ras proteins regulated 13 signaling pathways distinct from those regulated by classic Ras proteins. Closer study of an R-Ras regulated pathway containing the signaling protein ROCK1 showed that inhibition of either R-Ras, R-Ras2 or ROCK1 similarly impaired cellular migration and invasion and altered cellular morphology. Inhibition of R-Ras\/R-Ras2 and ROCK1 signaling also triggered the accumulation of abnormal intracellular vesicles, indicating that these signaling molecules regulate the movement of proteins and other molecules in the cellular interior.<\/jats:p>\n                \n                \n              <\/jats:sec>","DOI":"10.1186\/s12964-021-00773-4","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T12:02:53Z","timestamp":1631793773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["R-Ras subfamily proteins elicit distinct physiologic effects and phosphoproteome alterations in neurofibromin-null MPNST cells"],"prefix":"10.1186","volume":"19","author":[{"given":"Shannon M.","family":"Weber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Brossier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Prechtl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landon S.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie N.","family":"Brosius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody Fromm","family":"Longo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"773_CR1","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","volume":"347","author":"M Uhlen","year":"2015","unstructured":"Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, et al. Proteomics: tissue-based map of the human proteome. Science. 2015;347:1260419.","journal-title":"Science"},{"key":"773_CR2","doi-asserted-by":"publisher","first-page":"eaal3321","DOI":"10.1126\/science.aal3321","volume":"356","author":"PJ Thul","year":"2017","unstructured":"Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, Alm T, Asplund A, Bjork L, Breckels LM, et al. A subcellular map of the human proteome. Science. 2017;356:eaal3321.","journal-title":"Science"},{"key":"773_CR3","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1016\/j.bbamcr.2007.01.012","volume":"1773","author":"K Rajalingam","year":"2007","unstructured":"Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta. 2007;1773:1177\u201395.","journal-title":"Biochim Biophys Acta"},{"key":"773_CR4","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1126\/science.280.5366.1082","volume":"280","author":"JO Ebinu","year":"1998","unstructured":"Ebinu JO, Bottorff DA, Chan EY, Stang SL, Dunn RJ, Stone JC. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science. 1998;280:1082\u20136.","journal-title":"Science"},{"key":"773_CR5","doi-asserted-by":"publisher","first-page":"25542","DOI":"10.1016\/S0021-9258(19)74425-1","volume":"268","author":"S Orita","year":"1993","unstructured":"Orita S, Kaibuchi K, Kuroda S, Shimizu K, Nakanishi H, Takai Y. Comparison of kinetic properties between two mammalian ras p21 GDP\/GTP exchange proteins, ras guanine nucleotide-releasing factor and smg GDP dissociation stimulation. J Biol Chem. 1993;268:25542\u20136.","journal-title":"J Biol Chem"},{"key":"773_CR6","doi-asserted-by":"publisher","first-page":"6511","DOI":"10.1073\/pnas.89.14.6511","volume":"89","author":"D Bowtell","year":"1992","unstructured":"Bowtell D, Fu P, Simon M, Senior P. Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc Natl Acad Sci USA. 1992;89:6511\u20135.","journal-title":"Proc Natl Acad Sci USA"},{"key":"773_CR7","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1126\/science.2821624","volume":"238","author":"M Trahey","year":"1987","unstructured":"Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238:542\u20135.","journal-title":"Science"},{"key":"773_CR8","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/0092-8674(90)90094-U","volume":"60","author":"K Tanaka","year":"1990","unstructured":"Tanaka K, Nakafuku M, Satoh T, Marshall MS, Gibbs JB, Matsumoto K, Kaziro Y, Toh-e A. S cerevisiae genes IRA1 and IRA2 encode proteins that may be functionally equivalent to mammalian ras GTPase activating protein. Cell. 1990;60:803\u20137.","journal-title":"Cell"},{"key":"773_CR9","first-page":"4108","volume":"14","author":"SM Graham","year":"1994","unstructured":"Graham SM, Cox AD, Drivas G, Rush MG, D\u2019Eustachio P, Der CJ. Aberrant function of the Ras-related protein TC21\/R-Ras2 triggers malignant transformation. Mol Cell Biol. 1994;14:4108\u201315.","journal-title":"Mol Cell Biol"},{"key":"773_CR10","first-page":"3281","volume":"9","author":"AD Cox","year":"1994","unstructured":"Cox AD, Brtva TR, Lowe DG, Der CJ. R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells. Oncogene. 1994;9:3281\u20138.","journal-title":"Oncogene"},{"key":"773_CR11","doi-asserted-by":"publisher","first-page":"23850","DOI":"10.1074\/jbc.274.34.23850","volume":"274","author":"LA Quilliam","year":"1999","unstructured":"Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C. M-Ras\/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem. 1999;274:23850\u20137.","journal-title":"J Biol Chem"},{"key":"773_CR12","doi-asserted-by":"publisher","first-page":"7558","DOI":"10.1073\/pnas.91.16.7558","volume":"91","author":"AM Chan","year":"1994","unstructured":"Chan AM, Miki T, Meyers KA, Aaronson SA. A human oncogene of the RAS superfamily unmasked by expression cDNA cloning. Proc Natl Acad Sci USA. 1994;91:7558\u201362.","journal-title":"Proc Natl Acad Sci USA"},{"key":"773_CR13","first-page":"1255","volume":"11","author":"Y Huang","year":"1995","unstructured":"Huang Y, Saez R, Chao L, Santos E, Aaronson SA, Chan AM. A novel insertional mutation in the TC21 gene activates its transforming activity in a human leiomyosarcoma cell line. Oncogene. 1995;11:1255\u201360.","journal-title":"Oncogene"},{"key":"773_CR14","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/bjc.1998.490","volume":"78","author":"KT Barker","year":"1998","unstructured":"Barker KT, Crompton MR. Ras-related TC21 is activated by mutation in a breast cancer cell line, but infrequently in breast carcinomas in vivo. Br J Cancer. 1998;78:296\u2013300.","journal-title":"Br J Cancer"},{"key":"773_CR15","doi-asserted-by":"publisher","first-page":"27713","DOI":"10.1074\/jbc.M703037200","volume":"282","author":"M Erdogan","year":"2007","unstructured":"Erdogan M, Pozzi A, Bhowmick N, Moses HL, Zent R. Signaling pathways regulating TC21-induced tumorigenesis. J Biol Chem. 2007;282:27713\u201320.","journal-title":"J Biol Chem"},{"key":"773_CR16","doi-asserted-by":"publisher","first-page":"2107","DOI":"10.1038\/sj.onc.1202517","volume":"18","author":"SM Graham","year":"1999","unstructured":"Graham SM, Oldham SM, Martin CB, Drugan JK, Zohn IE, Campbell S, Der CJ. TC21 and Ras share indistinguishable transforming and differentiating activities. Oncogene. 1999;18:2107\u201316.","journal-title":"Oncogene"},{"key":"773_CR17","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1242\/jcs.02835","volume":"119","author":"AS Ada-Nguema","year":"2006","unstructured":"Ada-Nguema AS, Xenias H, Hofman JM, Wiggins CH, Sheetz MP, Keely PJ. The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCepsilon. J Cell Sci. 2006;119:1307\u201319.","journal-title":"J Cell Sci"},{"key":"773_CR18","doi-asserted-by":"publisher","first-page":"5692","DOI":"10.1038\/onc.2016.122","volume":"35","author":"C Fremin","year":"2016","unstructured":"Fremin C, Guegan JP, Plutoni C, Mahaffey J, Philips MR, Emery G, Meloche S. ERK1\/2-induced phosphorylation of R-Ras GTPases stimulates their oncogenic potential. Oncogene. 2016;35:5692\u20138.","journal-title":"Oncogene"},{"key":"773_CR19","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/sj.onc.1200815","volume":"14","author":"SY Huff","year":"1997","unstructured":"Huff SY, Quilliam LA, Cox AD, Der CJ. R-Ras is regulated by activators and effectors distinct from those that control Ras function. Oncogene. 1997;14:133\u201343.","journal-title":"Oncogene"},{"key":"773_CR20","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1038\/sj.onc.1201674","volume":"15","author":"A Kimmelman","year":"1997","unstructured":"Kimmelman A, Tolkacheva T, Lorenzi MV, Osada M, Chan AM. Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. Oncogene. 1997;15:2675\u201385.","journal-title":"Oncogene"},{"key":"773_CR21","doi-asserted-by":"publisher","first-page":"7932","DOI":"10.1158\/0008-5472.CAN-08-0866","volume":"68","author":"C Yi","year":"2008","unstructured":"Yi C, Wilker EW, Yaffe MB, Stemmer-Rachamimov A, Kissil JL. Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2. Can Res. 2008;68:7932\u20137.","journal-title":"Can Res"},{"key":"773_CR22","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.ccr.2009.05.009","volume":"16","author":"LT McGillicuddy","year":"2009","unstructured":"McGillicuddy LT, Fromm JA, Hollstein PE, Kubek S, Beroukhim R, De Raedt T, Johnson BW, Williams SM, Nghiemphu P, Liau LM, et al. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell. 2009;16:44\u201354.","journal-title":"Cancer Cell"},{"key":"773_CR23","doi-asserted-by":"publisher","first-page":"e7752","DOI":"10.1371\/journal.pone.0007752","volume":"4","author":"C Brennan","year":"2009","unstructured":"Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLOS ONE. 2009;4:e7752.","journal-title":"PLOS ONE"},{"key":"773_CR24","doi-asserted-by":"crossref","unstructured":"Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609\u2013615.","DOI":"10.1038\/nature10166"},{"key":"773_CR25","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1158\/1078-0432.CCR-09-2639","volume":"16","author":"B Parkin","year":"2010","unstructured":"Parkin B, Ouillette P, Wang Y, Liu Y, Wright W, Roulston D, Purkayastha A, Dressel A, Karp J, Bockenstedt P, et al. NF1 inactivation in adult acute myelogenous leukemia. Clin Cancer Res. 2010;16:4135\u201347.","journal-title":"Clin Cancer Res"},{"key":"773_CR26","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1158\/2159-8290.CD-13-0146","volume":"3","author":"PE Hollstein","year":"2013","unstructured":"Hollstein PE, Cichowski K. Identifying the ubiquitin ligase complex that regulates the NF1 tumor suppressor and Ras. Cancer Discov. 2013;3:880\u201393.","journal-title":"Cancer Discov"},{"key":"773_CR27","doi-asserted-by":"publisher","first-page":"20020","DOI":"10.1074\/jbc.M000981200","volume":"275","author":"Y Ohba","year":"2000","unstructured":"Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M. Regulatory proteins of R-Ras, TC21\/R-Ras2, and M-Ras\/R-Ras3. J Biol Chem. 2000;275:20020\u20136.","journal-title":"J Biol Chem"},{"key":"773_CR28","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1002\/glia.20776","volume":"56","author":"SL Carroll","year":"2008","unstructured":"Carroll SL, Ratner N. How does the Schwann cell lineage form tumors in NF1? Glia. 2008;56:1590\u2013605.","journal-title":"Glia"},{"key":"773_CR29","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.brainresbull.2011.08.005","volume":"88","author":"NM Brossier","year":"2011","unstructured":"Brossier NM, Carroll SL. Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system. Brain Res Bull. 2011;88:58.","journal-title":"Brain Res Bull"},{"key":"773_CR30","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/0092-8674(90)90149-9","volume":"63","author":"GF Xu","year":"1990","unstructured":"Xu GF, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R. Tamanoi F (1990) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell. 1990;63:835\u201341.","journal-title":"Cell"},{"key":"773_CR31","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/0092-8674(90)90150-D","volume":"63","author":"GA Martin","year":"1990","unstructured":"Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O\u2019Connell P, Cawthon RM, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990;63:843\u20139.","journal-title":"Cell"},{"key":"773_CR32","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/0092-8674(90)90151-4","volume":"63","author":"R Ballester","year":"1990","unstructured":"Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990;63:851\u20139.","journal-title":"Cell"},{"key":"773_CR33","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1097\/NEN.0000000000000201","volume":"74","author":"NM Brossier","year":"2015","unstructured":"Brossier NM, Prechtl AM, Longo JF, Barnes S, Wilson LS, Byer SJ, Brosius SN, Carroll SL. Classic ras proteins promote proliferation and survival via distinct phosphoproteome alterations in neurofibromin-null malignant peripheral nerve sheath tumor cells. J Neuropathol Exp Neurol. 2015;74:568\u201386.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"Pt 2","key":"773_CR34","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1042\/bj3000303","volume":"300","author":"M Spaargaren","year":"1994","unstructured":"Spaargaren M, Martin GA, McCormick F, Fernandez-Sarabia MJ, Bischoff JR. The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner. Biochem J. 1994;300(Pt 2):303\u20137.","journal-title":"Biochem J"},{"key":"773_CR35","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0092-8674(00)81082-X","volume":"85","author":"Z Zhang","year":"1996","unstructured":"Zhang Z, Vuori K, Wang H, Reed JC, Ruoslahti E. Integrin activation by R-ras. Cell. 1996;85:61\u20139.","journal-title":"Cell"},{"key":"773_CR36","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0960-9822(06)00028-5","volume":"7","author":"BM Marte","year":"1997","unstructured":"Marte BM, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J. R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr Biol. 1997;7:63\u201370.","journal-title":"Curr Biol"},{"key":"773_CR37","doi-asserted-by":"publisher","first-page":"29079","DOI":"10.1074\/jbc.M102001200","volume":"276","author":"M Hamilton","year":"2001","unstructured":"Hamilton M, Liao J, Cathcart MK, Wolfman A. Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. J Biol Chem. 2001;276:29079\u201390.","journal-title":"J Biol Chem"},{"key":"773_CR38","doi-asserted-by":"publisher","first-page":"29730","DOI":"10.1074\/jbc.M600668200","volume":"281","author":"J Liao","year":"2006","unstructured":"Liao J, Planchon SM, Wolfman JC, Wolfman A. Growth factor-dependent AKT activation and cell migration requires the function of c-K(B)-Ras versus other cellular ras isoforms. J Biol Chem. 2006;281:29730\u20138.","journal-title":"J Biol Chem"},{"key":"773_CR39","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1038\/ng.115","volume":"40","author":"KM Haigis","year":"2008","unstructured":"Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008;40:600\u20138.","journal-title":"Nat Genet"},{"key":"773_CR40","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/sj.onc.1207075","volume":"23","author":"Y Huang","year":"2004","unstructured":"Huang Y, Rangwala F, Fulkerson PC, Ling B, Reed E, Cox AD, Kamholz J, Ratner N. Role of TC21\/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells. Oncogene. 2004;23:368\u201378.","journal-title":"Oncogene"},{"key":"773_CR41","doi-asserted-by":"publisher","first-page":"5589","DOI":"10.1038\/sj.onc.1208730","volume":"24","author":"MS Stonecypher","year":"2005","unstructured":"Stonecypher MS, Byer SJ, Grizzle WE, Carroll SL. Activation of the neuregulin-1\/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors. Oncogene. 2005;24:5589\u2013605.","journal-title":"Oncogene"},{"key":"773_CR42","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1097\/01.jnen.0000199575.93794.2f","volume":"65","author":"MS Stonecypher","year":"2006","unstructured":"Stonecypher MS, Chaudhury AR, Byer SJ, Carroll SL. Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis. J Neuropathol Exp Neurol. 2006;65:162\u201375.","journal-title":"J Neuropathol Exp Neurol"},{"key":"773_CR43","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1093\/neuonc\/noq146","volume":"13","author":"SJ Byer","year":"2011","unstructured":"Byer SJ, Eckert JM, Brossier NM, Clodfelder-Miller BJ, Turk AN, Carroll AJ, Kappes JC, Zinn KR, Prasain JK, Carroll SL. Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor-independent manner. Neuro Oncol. 2011;13:28\u201341.","journal-title":"Neuro Oncol"},{"key":"773_CR44","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/S0378-1119(99)00045-1","volume":"229","author":"CA Strathdee","year":"1999","unstructured":"Strathdee CA, McLeod MR, Hall JR. Efficient control of tetracycline-responsive gene expression from an autoregulated bi-directional expression vector. Gene. 1999;229:21\u20139.","journal-title":"Gene"},{"key":"773_CR45","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1002\/glia.10232","volume":"43","author":"PW Frohnert","year":"2003","unstructured":"Frohnert PW, Stonecypher MS, Carroll SL. Constitutive activation of the neuregulin-1\/ErbB receptor signaling pathway is essential for the proliferation of a neoplastic Schwann cell line. Glia. 2003;43:104\u201318.","journal-title":"Glia"},{"key":"773_CR46","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1093\/jnen\/62.5.520","volume":"62","author":"PW Frohnert","year":"2003","unstructured":"Frohnert PW, Stonecypher MS, Carroll SL. Lysophosphatidic acid promotes the proliferation of adult Schwann cells isolated from axotomized sciatic nerve. J Neuropathol Exp Neurol. 2003;62:520\u20139.","journal-title":"J Neuropathol Exp Neurol"},{"key":"773_CR47","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1002\/glia.20866","volume":"57","author":"JM Eckert","year":"2009","unstructured":"Eckert JM, Byer SJ, Clodfelder-Miller BJ, Carroll SL. Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells. Glia. 2009;57:1501\u201320.","journal-title":"Glia"},{"key":"773_CR48","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671\u20135.","journal-title":"Nat Methods"},{"key":"773_CR49","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1158\/0008-5472.CAN-11-1818","volume":"71","author":"TT Dang","year":"2011","unstructured":"Dang TT, Prechtl AM, Pearson GW. Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion. Cancer Res. 2011;71:6857\u201366.","journal-title":"Cancer Res"},{"key":"773_CR50","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1016\/j.ajpath.2021.05.008","volume":"191","author":"SM Weber","year":"2021","unstructured":"Weber SM, Carroll SL. The role of R-Ras proteins in normal and pathologic migration and morphologic change. Am J Pathol. 2021;191:1499\u2013510. https:\/\/doi.org\/10.1016\/j.ajpath.2021.05.008.","journal-title":"Am J Pathol"},{"key":"773_CR51","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1016\/S0021-9258(18)54022-9","volume":"268","author":"J John","year":"1993","unstructured":"John J, Rensland H, Schlichting I, Vetter I, Borasio GD, Goody RS, Wittinghofer A. Kinetic and structural analysis of the Mg(2+)-binding site of the guanine nucleotide-binding protein p21H-ras. J Biol Chem. 1993;268:923\u20139.","journal-title":"J Biol Chem"},{"key":"773_CR52","doi-asserted-by":"publisher","first-page":"5533","DOI":"10.1158\/1078-0432.CCR-06-0792","volume":"12","author":"B Barkan","year":"2006","unstructured":"Barkan B, Starinsky S, Friedman E, Stein R, Kloog Y. The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1. Clin Cancer Res. 2006;12:5533\u201342.","journal-title":"Clin Cancer Res"},{"key":"773_CR53","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1083\/jcb.129.4.1103","volume":"129","author":"HG Wang","year":"1995","unstructured":"Wang HG, Millan JA, Cox AD, Der CJ, Rapp UR, Beck T, Zha H, Reed JC. R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl-2 suppressible mechanism. J Cell Biol. 1995;129:1103\u201314.","journal-title":"J Cell Biol"},{"issue":"Pt 2","key":"773_CR54","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1042\/bj3000303","volume":"300","author":"M Spaargaren","year":"1994","unstructured":"Spaargaren M, Martin GA, McCormick F, Fernandez-Sarabia MJ, Bischoff JR. The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner. Biochem J. 1994;300(Pt 2):303\u20137.","journal-title":"Biochem J"},{"key":"773_CR55","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0960-9822(06)00028-5","volume":"7","author":"BM Marte","year":"1997","unstructured":"Marte BM, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J. R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr Biol. 1997;7:63\u201370.","journal-title":"Curr Biol"},{"key":"773_CR56","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1093\/emboj\/18.5.1270","volume":"18","author":"M Rosario","year":"1999","unstructured":"Rosario M, Paterson HF, Marshall CJ. Activation of the Raf\/MAP kinase cascade by the Ras-related protein TC21 is required for the TC21-mediated transformation of NIH 3T3 cells. EMBO J. 1999;18:1270\u20139.","journal-title":"EMBO J"},{"key":"773_CR57","doi-asserted-by":"publisher","first-page":"5860","DOI":"10.1038\/sj.onc.1202968","volume":"18","author":"N Movilla","year":"1999","unstructured":"Movilla N, Crespo P, Bustelo XR. Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins. Oncogene. 1999;18:5860\u20139.","journal-title":"Oncogene"},{"key":"773_CR58","doi-asserted-by":"publisher","first-page":"6132","DOI":"10.1128\/MCB.16.11.6132","volume":"16","author":"SM Graham","year":"1996","unstructured":"Graham SM, Vojtek AB, Huff SY, Cox AD, Clark GJ, Cooper JA, Der CJ. TC21 causes transformation by Raf-independent signaling pathways. Mol Cell Biol. 1996;16:6132\u201340.","journal-title":"Mol Cell Biol"},{"key":"773_CR59","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/31729","volume":"393","author":"S Arber","year":"1998","unstructured":"Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O, Caroni P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature. 1998;393:805\u20139.","journal-title":"Nature"},{"key":"773_CR60","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1126\/science.285.5429.895","volume":"285","author":"M Maekawa","year":"1999","unstructured":"Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999;285:895\u20138.","journal-title":"Science"},{"key":"773_CR61","doi-asserted-by":"publisher","first-page":"5374","DOI":"10.1529\/biophysj.108.133116","volume":"95","author":"PP Provenzano","year":"2008","unstructured":"Provenzano PP, Inman DR, Eliceiri KW, Trier SM, Keely PJ. Contact guidance mediated three-dimensional cell migration is regulated by Rho\/ROCK-dependent matrix reorganization. Biophys J. 2008;95:5374\u201384.","journal-title":"Biophys J"},{"key":"773_CR62","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1083\/jcb.151.7.1549","volume":"151","author":"AL Berrier","year":"2000","unstructured":"Berrier AL, Mastrangelo AM, Downward J, Ginsberg M, LaFlamme SE. Activated R-ras, Rac1, PI 3-kinase and PKCepsilon can each restore cell spreading inhibited by isolated integrin beta1 cytoplasmic domains. J Cell Biol. 2000;151:1549\u201360.","journal-title":"J Cell Biol"},{"key":"773_CR63","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1126\/science.1091325","volume":"303","author":"AF Palazzo","year":"2004","unstructured":"Palazzo AF, Eng CH, Schlaepfer DD, Marcantonio EE, Gundersen GG. Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling. Science. 2004;303:836\u20139.","journal-title":"Science"},{"key":"773_CR64","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.tcb.2004.12.006","volume":"15","author":"T Watanabe","year":"2005","unstructured":"Watanabe T, Noritake J, Kaibuchi K. Regulation of microtubules in cell migration. Trends Cell Biol. 2005;15:76\u201383.","journal-title":"Trends Cell Biol"},{"key":"773_CR65","doi-asserted-by":"publisher","first-page":"28200","DOI":"10.1074\/jbc.M110.147546","volume":"285","author":"I Oinuma","year":"2010","unstructured":"Oinuma I, Ito Y, Katoh H, Negishi M. Semaphorin 4D\/Plexin-B1 stimulates PTEN activity through R-Ras GTPase-activating protein activity, inducing growth cone collapse in hippocampal neurons. J Biol Chem. 2010;285:28200\u20139.","journal-title":"J Biol Chem"},{"key":"773_CR66","doi-asserted-by":"publisher","first-page":"11473","DOI":"10.1523\/JNEUROSCI.3257-04.2004","volume":"24","author":"I Oinuma","year":"2004","unstructured":"Oinuma I, Katoh H, Negishi M. Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci. 2004;24:11473\u201380.","journal-title":"J Neurosci"},{"key":"773_CR67","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/nrm2799","volume":"10","author":"PT Caswell","year":"2009","unstructured":"Caswell PT, Vadrevu S, Norman JC. Integrins: masters and slaves of endocytic transport. Nat Rev Mol Cell Biol. 2009;10:843\u201353.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"773_CR68","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1083\/jcb.200508204","volume":"173","author":"I Oinuma","year":"2006","unstructured":"Oinuma I, Katoh H, Negishi M. Semaphorin 4D\/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity. J Cell Biol. 2006;173:601\u201313.","journal-title":"J Cell Biol"},{"key":"773_CR69","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1083\/jcb.145.5.1077","volume":"145","author":"PJ Keely","year":"1999","unstructured":"Keely PJ, Rusyn EV, Cox AD, Parise LV. R-Ras signals through specific integrin alpha cytoplasmic domains to promote migration and invasion of breast epithelial cells. J Cell Biol. 1999;145:1077\u201388.","journal-title":"J Cell Biol"},{"key":"773_CR70","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/S0014-5793(97)00139-7","volume":"404","author":"S Osada","year":"1997","unstructured":"Osada S, Izawa M, Koyama T, Hirai S, Ohno S. A domain containing the Cdc42\/Rac interactive binding (CRIB) region of p65PAK inhibits transcriptional activation and cell transformation mediated by the Ras-Rac pathway. FEBS Lett. 1997;404:227\u201333.","journal-title":"FEBS Lett"},{"key":"773_CR71","doi-asserted-by":"publisher","first-page":"6333","DOI":"10.1128\/MCB.19.9.6333","volume":"19","author":"M Osada","year":"1999","unstructured":"Osada M, Tolkacheva T, Li W, Chan TO, Tsichlis PN, Saez R, Kimmelman AC, Chan AM. Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival. Mol Cell Biol. 1999;19:6333\u201344.","journal-title":"Mol Cell Biol"},{"key":"773_CR72","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1083\/jcb.200603111","volume":"174","author":"LE Goldfinger","year":"2006","unstructured":"Goldfinger LE, Ptak C, Jeffery ED, Shabanowitz J, Hunt DF, Ginsberg MH. RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration. J Cell Biol. 2006;174:877\u201388.","journal-title":"J Cell Biol"},{"key":"773_CR73","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1101\/gad.192351.112","volume":"26","author":"C D'Souza-Schorey","year":"2012","unstructured":"D\u2019Souza-Schorey C, Clancy JW. Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 2012;26:1287\u201399.","journal-title":"Genes Dev"},{"key":"773_CR74","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cellsig.2012.09.010","volume":"25","author":"A Mleczak","year":"2013","unstructured":"Mleczak A, Millar S, Tooze SA, Olson MF, Chan EY. Regulation of autophagosome formation by Rho kinase. Cell Signal. 2013;25:1\u201311.","journal-title":"Cell Signal"},{"key":"773_CR75","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1091\/mbc.e04-04-0277","volume":"16","author":"MA Wozniak","year":"2005","unstructured":"Wozniak MA, Kwong L, Chodniewicz D, Klemke RL, Keely PJ. R-Ras controls membrane protrusion and cell migration through the spatial regulation of Rac and Rho. Mol Biol Cell. 2005;16:84\u201396.","journal-title":"Mol Biol Cell"},{"key":"773_CR76","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1002\/pro.3711","volume":"29","author":"M Kanehisa","year":"2020","unstructured":"Kanehisa M, Sato Y. KEGG Mapper for inferring cellular functions from protein sequences. Protein Sci. 2020;29:28\u201335.","journal-title":"Protein Sci"},{"key":"773_CR77","doi-asserted-by":"publisher","first-page":"D590","DOI":"10.1093\/nar\/gky962","volume":"47","author":"M Kanehisa","year":"2019","unstructured":"Kanehisa M, Sato Y, Furumichi M, Morishima K, Tanabe M. New approach for understanding genome variations in KEGG. Nucleic Acids Res. 2019;47:D590\u20135.","journal-title":"Nucleic Acids Res"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-021-00773-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-021-00773-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-021-00773-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T13:11:50Z","timestamp":1631797910000},"score":1,"resource":{"primary":{"URL":"https:\/\/biosignaling.biomedcentral.com\/articles\/10.1186\/s12964-021-00773-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,16]]},"references-count":77,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["773"],"URL":"https:\/\/doi.org\/10.1186\/s12964-021-00773-4","relation":{},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,16]]},"assertion":[{"value":"17 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"95"}}