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Subcellular localization

Ciliary associated gene, Nuclear speckles

Functional category

• Non-motile cilium / primary cilium
• Ciliary assembly/disassembly

Function

κB-Ras/RalGAP complexes limit the activity of Ral GTPases, which function in EGFR/Ras signaling. RalGAP expression is down-regulated in pancreatic cancer, however, the role of RalGAP and Ral GTPases in tumor development in vivo remained unclear. Here, we show that pancreatic RalGAPβ deficiency alone is sufficient to induce inflammation and neoplasia in vivo. We identify that this phenotype is triggered by disturbance of the secretory pathway and polarized exocytosis in acinar cells, demonstrating that RalGAP complexes uphold spatial control of Ral activity. We furthermore show that RALGAPβ deficiency results in defective primary cilium assembly, a process required for efficient acinar regeneration upon inflammation. Only primary cilium formation depends on κB-Ras proteins, suggesting that κB-Ras proteins are not essential for all RalGAP complex-controlled processes. In combination with an oncogenic KRASG12D mutation, RalGAPβ deficiency leads to a dramatic shortening of tumor latency and median survival. Our results highlight an important role of RalGAP/Ral signaling in upholding acinar cell identity and preventing pancreatic cancer development. Based on this gene expression analysis, we performed histological stainings and detected primary cilia in WT but not RGβKO acini 24 h after cerulein treatment (Fig S6D). However, primary cilium numbers were so low, likely because of the late time point of analysis, that a reliable quantification was not possible. We therefore decided to analyze whether we could detect a defect in primary cilium formation in the RalGAPβ-deficient duct cells in unchallenged mice, assuming that such a role of Ral GTPase signaling would likely be conserved between cell types. Indeed, the number of ductal cells with primary cilia was significantly reduced in RGβKO animals (Fig 6B and C)(40490362).