Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

SignificanceTrypanosoma brucei is a highly invasive pathogen capable of penetrating deeply into host tissues. To understand how flagellar motility facilitates cell penetration, we used cryo-electron tomography (cryo-ET) to visualize two genetically anucleate mutants with different flagellar motility behaviors. We found that the T. brucei cell body is highly deformable as defined by changes in cytoskeletal twist and spacing, in response to flagellar beating and environmental conditions. Based on the cryo-ET models, we proposed a mechanism of how flagellum motility is coupled to cell shape changes, which may facilitate penetration through size-limiting barriers.

Sperm flagellar protein 1 (Spef1, also known as CLAMP) is a microtubule-associated protein involved in various microtubule-related functions from ciliary motility to polarized cell movement and planar cell polarity. In Trypanosoma brucei, the causative agent of trypanosomiasis, a single Spef1 ortholog (TbSpef1) is associated with a microtubule quartet (MtQ), which is in close association with several single-copied organelles and is required for their coordinated biogenesis during the cell cycle. Here, we investigated the interaction network of TbSpef1 using BioID, a proximity-dependent protein-protein interaction screening method. Characterization of selected candidates provided a molecular description of TbSpef1-MtQ interactions with nearby cytoskeletal structures. Of particular interest, we identified a new basal body protein TbSAF1, which is required for TbSpef1-MtQ anchorage to the basal bodies. The results demonstrate that MtQ-basal body anchorage is critical for the spatial organization of cytoskeletal organelles, as well as the morphology of the membrane-bound flagellar pocket where endocytosis takes place in this parasite. IMPORTANCE Trypanosoma brucei contains a large array of single-copied organelles and structures. Through extensive interorganelle connections, these structures replicate and divide following a strict temporal and spatial order. A microtubule quartet (MtQ) originates from the basal bodies and extends toward the anterior end of the cell, stringing several cytoskeletal structures together along its path. In this study, we examined the interaction network of TbSpef1, the only protein specifically located to the MtQ. We identified an interaction between TbSpef1 and a basal body protein TbSAF1, which is required for MtQ anchorage to the basal bodies. This study thus provides the first molecular description of MtQ association with the basal bodies, since the discovery of this association ∼30 years ago. The results also reveal a general mechanism of the evolutionarily conserved Spef1/CLAMP, which achieves specific cellular functions via their conserved microtubule functions and their diverse molecular interaction networks.

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Arl13b and Arl3 are ciliary GTPases implicated in human Joubert Syndrome, affecting ciliary membrane and axoneme organization. Although the mechanism of Arl13b as a guanine nucleotide exchange factor (GEF) of Arl3 and the function of Arl13b and Arl3 in ciliary membrane protein transport are well established, their role in axoneme biogenesis is unclear. InTrypanosoma brucei, TbArl13 acts as a GEF for two distinct TbArl3 proteins, TbArl3A and TbArl3C. Here, we identified theT. bruceihomolog of ODA16, a cargo adapter facilitating intraflagellar transport (IFT) of motile ciliary components, as an effector of both TbArl3A and TbArl3C. Depletion of TbArl3 GTPases stabilized TbODA16 interaction with IFT, while active TbArl3 variants displaced TbODA16 from IFT, demonstrating a mechanism of TbArl3 in motile ciliary cargo transport.