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Protein kinases take the center stage in numerous signaling pathways by phosphorylating compartmentalized protein substrates for controlling cell proliferation, cell cycle and metabolism. Kinase dysfunctions have been linked to numerous human diseases such as cancer. This has led to the development of kinase inhibitors which aim to target oncogenic kinase activities. The specificity of the cancer blockers depends on the range of targeted kinases. Therefore, the question arises of how cell-type-specific off-target effects impair the specificities of cancer drugs. Blockade of kinase activities has been shown to converge on the energetic organelle, the mitochondria. In this review, we highlight examples of selected major kinases that impact mitochondrial signaling. Further, we discuss pharmacological strategies to target kinase activities linked to cancer progression and redirecting mitochondrial function. Finally, we propose that cell-based recordings of mitochondrial bioenergetic states might predict off-target or identify specific on-target effects of kinase inhibitors.

Small non-coding RNAs (sRNAs) are expected to have pivotal roles in the adaptive responses underlying symbiosis of nitrogen-fixing rhizobia with legumes. Here, we provide primary insights into the function and activity mechanism of the Sinorhizobium meliloti trans-sRNA NfeR1 (Nodule Formation Efficiency RNA). Northern blot probing and transcription tracking with fluorescent promoter-reporter fusions unveiled high nfeR1 expression in response to salt stress and throughout the symbiotic interaction. The strength and differential regulation of nfeR1 transcription are conferred by a motif, which is conserved in nfeR1 promoter regions in α-proteobacteria. NfeR1 loss-of-function compromised osmoadaptation of free-living bacteria, whilst causing misregulation of salt-responsive genes related to stress adaptation, osmolytes catabolism and membrane trafficking. Nodulation tests revealed that lack of NfeR1 affected competitiveness, infectivity, nodule development and symbiotic efficiency of S. meliloti on alfalfa roots. Comparative computer predictions and a genetic reporter assay evidenced a redundant role of three identical NfeR1 unpaired anti Shine-Dalgarno motifs for targeting and downregulation of translation of multiple mRNAs from transporter genes. Our data provide genetic evidence of the hyperosmotic conditions of the endosymbiotic compartments. NfeR1-mediated gene regulation in response to this cue could contribute to coordinate nutrient uptake with the metabolic reprogramming concomitant to symbiotic transitions., This work was funded by the ERDF‐cofinanced grant BFU2013‐48282‐C2‐2‐P from the Spanish Ministerio de Economía y Competitividad, to J.I.J.‐Z., and by a DAAD Concerted Spain‐Germany Action to J.I.J.‐Z. and A.B. M.R. and A.P. were funded by contracts from the Ministerio de Economía y Competitividad (Programa de Formación Post‐doctoral, Juan de la Cierva) and CSIC (JAEDoc program), respectively. A.P. was also supported by an EMBO short‐term fellowship. N.I.G.‐T. was recipient of a JAEIntro CSIC grant. We acknowledge advice of Ma José Soto on the interpretation of the results of symbiotic tests. The authors thank Ascensión Martos and Barbara Herte for technical assistance, Myriam Charpentier (John Innes Centre) for kindly providing M. truncatula line 416K plant seeds, and the core facilities of EEZ‐CSIC for routine sequencing of plasmid constructs. The authors declare that they have no conflict of interest

The primary cilium emanates from the cell surface of growth-arrested cells and plays a central role in vertebrate development and tissue homeostasis. The mechanisms that control ciliogenesis have been extensively explored. However, the intersection between GPCR signaling and the ubiquitin pathway in the control of cilium stability are unknown. Here we observe that cAMP elevation promotes cilia resorption. At centriolar satellites, we identify a multimeric complex nucleated by PCM1 that includes two kinases, NEK10 and PKA, and the E3 ubiquitin ligase CHIP. We show that NEK10 is essential for ciliogenesis in mammals and for the development of medaka fish. PKA phosphorylation primes NEK10 for CHIP-mediated ubiquitination and proteolysis resulting in cilia resorption. Disarrangement of this control mechanism occurs in proliferative and genetic disorders. These findings unveil a pericentriolar kinase signalosome that efficiently links the cAMP cascade with the ubiquitin-proteasome system, thereby controlling essential aspects of ciliogenesis., The mechanisms that control ciliogenesis have been extensively explored however the signaling mechanisms that control cilium stability remain unclear. Here the authors show that GPCR signaling regulates cilia resorption via the ubiquitin-proteasome system.