GMF was later localized to

GMFβ was later localized to the cytosol of primary astrocytes and glioma cell lines [67], prompting investigations into its involvement in intracellular signaling. It was found that PKA phosphorylation of GMFβ inhibits the ERK1/2 branch of the MAP kinase pathway [73], yet activates the stress-responsive p38 pathway [64]. GMFβ-stimulated p38 signaling in turn induced NF-κB-mediated transcription, leading to secretion of: (i) growth factors such as BDNF and NGF to promote neurite outgrowth and neuroprotection, 74, 75, 76, 77, and (ii) proinflammatory cytokines such as TNF-α and IFN-γ 78, 79. These observations, combined with studies on GMFβ−/− knockout mice, have suggested that GMFβ has neuroprotective roles in Alzheimer’s disease and Parkinson’s disease (Box 2). How can we reconcile these observations for GMF with its well-defined biochemical and cellular functions in Alamethicin network remodeling? One possibility is that GMF signaling and cytoskeletal functions are mediated by distinct isoforms, GMFβ and GMFγ, respectively. However, the striking similarity in structure between GMFβ and GMFγ, (Figure 1) argues against this, as do studies showing that GMFβ and GMFγ both regulate actin (10, 11, 14, 25, 42 M.O. Sweeney, PhD Thesis, Brandeis University, 2014). Further, at least one study has indicated that GMFγ, like GMFβ, functions in MAP kinase signaling [41]. Therefore, there is little evidence to support a ‘separate isoforms’ model. Alternatively, signaling and cytoskeletal functions of GMF could be integrated, such that association of GMF with actin networks spatially regulates MAP kinase signaling. This integration could lead to GMF availability for signaling being dependent on the local state of actin turnover, making MAP kinase signaling responsive to actin dynamics. Reciprocally, GMF modification by signaling pathways could affect its availability for actin remodeling. In fact, GMF inhibits ERK signaling [73], and ERK phosphorylates/activates components of the WAVE regulatory complex to promote Arp2/3-mediated actin assembly at the leading edge [80]. Therefore, GMF enrichment in retracting lamellipodia could not only promote debranching and direct Arp2/3 inhibition, but also indirectly block new actin assembly by inhibiting ERK signaling to WAVE (Figure 2).
Concluding Remarks and Future Directions Over the past 40 years, our view of GMF has evolved from a secreted factor that promotes cellular differentiation, to an intracellular signaling protein, to a bona fide component of cellular actin networks with highly specific roles in controlling Arp2/3 complex activities and actin filament remodeling. This leaves it uncertain why GMF was initially identified in the extracellular space, or how it was able to induce cell differentiation, and whether this involved its internalization into cells. Future work is also needed to investigate the cross-relationships and interdependence of GMF functions in actin regulation and signaling. In addition, there are a number of questions yet to be answered about GMF mechanism and function in governing Arp2/3 complex activity, alone and in combination with other proteins (see Outstanding Questions). These mysteries deserve new attention, using modern cell biological techniques and taking advantage of separation-of-function mutations now available, to rigorously test the in vivo importance of these suggested functions. This will also be a crucial step in understanding which functions of GMF underlie its genetically demonstrated neuroprotective and anti-inflammatory functions.
Acknowledgments
Synaptic deficiency in autism spectrum disorder Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect the ability of individuals to communicate and interact with others. ASD is characterized by impaired social interactions, communication deficits, and repetitive behaviors. ASD is typically diagnosed during the first 3years of life, a period of extensive neurite formation, synaptogenesis and refinement (Huttenlocher & Dabholkar, 1997; Zoghbi & Bear, 2012; Stamou et al., 2013; McGee et al., 2014). Family and twin studies have revealed that ASD has a strong genetic component, with numerous genes being affected. In addition to mutations inherited from parents, many ASD-associated mutations are rare protein disrupting de novo mutations that have arisen in the germline. Mutations can be copy-number variants (CNVs) or single-base-pair mutations (de la Torre-Ubieta et al., 2016). By definition, CNVs are deleted or duplicated segments of DNA (>1000basepairs) that are thought to be involved in the pathogenesis of a wide range of human diseases, including ASD. At least six recurrent CNVs are among the most frequently identified genetic contributors to ASD (Sanders et al., 2015). Overall, there seems to be an enrichment in ‘likely gene-disrupting’ mutations (LGDs; nonsense, frameshift and splice site mutations that often result in the production of truncated proteins) in individuals with ASD as compared to their healthy relatives or to other unaffected individuals (de la Torre-Ubieta et al., 2016).