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Abstract

The evolutionary conserved Erk Mapk (mitogen activated protein kinase) pathway coordinates essential cellular functions including cell survival, division, growth, motility and differentiation [9,61]. To execute such intricate functions, Erk regulates transcription factors impinging on gene expression, and a vast assortment of cytosolic and nuclear substrates coordinating other aspects of cellular metabolism. As part of the polyvalent nature of this pathway’s functionality, Erk Mapk has been firmly established as a growth promoter in different contexts [3,69,70,151-153]. However, despite a vast literature, the nature of the effectors and interactions underlying Mapk-driven growth remains poorly understood. Therefore, the question that sparked this study was- how does Mapk drive growth? Does it invoke a single growth mechanism or (like other metabolic decisions) it relies on the concerted action of multiple effectors acting at different stages and/or in different developmental contexts? Our study brings forward a model according to which Erk Mapk may promote growth in insect cells via two mechanisms. A first Mapkapk-driven mechanism (Mapk activated protein kinase) that may directly promote translation or activate other effectors (like ToR) in order to do so. And a second ToRC1-dependent mechanism (target of rapamycin complex1) which promotes biosynthetic pathways and eventually growth. ToRC1 integrates five major inputs (growth factors, amino acids, energy, stress and oxygen) and accordingly regulates anabolic pathways (like protein and lipid synthesis) as well as catabolic pathways (like autophagy) [154]. Our study supports a ToR-dependent mechanism as we learned that in cultured insect cells, Ras-Mapk appears to be sufficient and required for ToRC1 activation (II-2, III-4/5), while in the animal’s intestine Ras-Mapk depends on ToRC1 activity to fully promote growth (II-3,III-6). Furthermore, we found that Ras-Mapk activation in the developing intestine acts as a potent growth and proliferation promoter, even under conditions of protein starvation (II-4, III-6)—a phenotype previously attributed to ToRC1 [47]. Consistently, both Erk and one of its targets (Rsk) were found to positively regulate ToRC1 in mammalian cells [30-36]. As mentioned, Mapk pathways are firmly wired into the cell’s metabolic framework by phosphorylating a varied assortment of target proteins in the nucleus as in the cytoplasm. Among these substrates are the Mapkapks [10,11]. Our study also supports a Mapkapk-dependent growth mechanism, as our in vitro assays reveal that three Mapkapks (Mnk, Rsk, Msk) are required for insect cell growth under normal and growth factor stimulated conditions (II-1, III-2/3). Furthermore, mammalian studies have attributed a significant extent of Mapk functionalities to the activation of downstream Mapkapks (III-3). There is hardly any cellular stimulus that doesn’t feed into Mapk and ToR pathways. It is easy to see how connecting them would be advantageous not only for tissue homeostasis and regeneration but also for keeping developmental and metabolic decisions in sync. Mapk and ToR pathways are often hijacked by different cancers to initiate and grow tumors, and eventually metastasize. Dysregulation of Mapkapks is also associated with multiple human diseases including cancer (I-3). The ability of Ras-Mapk to drive growth and initiate tumors has been exploited in designing fly-based screening platforms for potential anticancer agents (I-5). The significance of our study and others is therefore far reaching, not only for understanding of how cells integrate multiple inputs to grow and dynamically coordinate developmental with metabolic decisions, but also towards designing more effective therapies targeting tumor growth.