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© 2020 by the authors ; Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other posttranslational modifications can contribute to the regulation of the biological activity of this protein. Here, we show that Vav1 becomes acetylated on lysine residues in a stimulation- and SH2 domain-dependent manner. Using a collection of both acetylation- and deacetylation-mimicking mutants, we show that the acetylation of four lysine residues (Lys222, Lys252, Lys587, and Lys716) leads to the downmodulation of the adaptor function of Vav1 that triggers the stimulation of the nuclear factor of activated T cells (NFAT). These sites belong to two functional subclasses according to mechanistic criteria. We have also unveiled additional acetylation sites potentially involved in either the stimulation (Lys782) or the downmodulation (Lys335, Lys374) of specific Vav1-dependent downstream responses. Collectively, these results indicate that Nε-lysine acetylation can play variegated roles in the regulation of Vav1 signaling. Unlike the case of the tyrosine phosphorylation step, this new regulatory layer is not conserved in other Vav family paralogs. ; X.R.B. is supported by grants from the Castilla-León Government (CLC-2017-01), the Spanish Ministry of Science, Innovation, and Universities (MSIU) (RTI2018-096481-B-I00), and the Spanish Association against Cancer (GC16173472GARC). X.R.B.'s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Ministry of Education of the Castilla-León Government (CLC-2017-01). S.R.-F. and L.F.L.-M. contracts have been supported by funding from the MISIU (S.R.-F., BES-2013-063573), the Spanish Ministry of Education, Culture, and Sports (L.F.L.-M., FPU13/02923), and the CLC-2017-01 grant (S.R.-F. and L.F.L.-M.). L.F.-N. is supported by the Salamanca local section of the Spanish Association for Cancer Research. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.

© 2021 The Authors. ; Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities. ; The X.R.B.'s project leading to these results has received funding from "la Caixa" Banking Foundation (HR20-00164), the Castilla-León autonomous government (CSI252P18, CSI145P20, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-100), and the Spanish Association against Cancer (GC16173472GARC). J.R.-V. received funding from the Carlos III Health Institute (PI20/01724). X.R.B.'s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). J.R-V. is supported by a senior postdoctoral contract of the Spanish Association against Cancer. L.F.-N contract has been supported by the Salamanca local section of the Spanish Association against Cancer. S.R.-F. and L.F.L.-M. contracts have been mostly supported by funding from the MSI (BES-2013-063573) and the Spanish Ministry of Education, Culture and Sports (L.F.L.-M., FPU13/02923), respectively. Subsequently, they both were supported by the CLC-2017-01 grant. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.