Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding

Abstract

Microtubule-associated protein Tau is known to bind to and stabilize microtubules, thereby regulating microtubule dynamics. However, recent evidence has indicated that Tau can also interact with various components of intracellular signaling pathways, leading to the possibility that Tau might have a role in signal transduction. Here we provide evidence that during growth factor stimulation of neuronal cells, Tau has functions in advance of the neurite elongation stage. Using Tau-depleted neuronal cell lines, we demonstrate that Tau is required for neurite initiation in a manner that does not involve its microtubule binding function. In addition, we demonstrate that Tau potentiates AP-1 transcription factor activation in response to nerve growth factor (NGF). The effect of Tau on AP-1 activation is mediated through its ability to potentiate the activation of mitogen-activated protein kinase (MAPK), which occurs in response to both NGF and epidermal growth factor. Phosphorylation of Tau at Thr-231 also occurs in response to NGF and is required for Tau to impact on MAPK signaling, whereas the ability of Tau to bind to microtubules is not required. Together, these findings indicate a new functional role for Tau in early neuronal development independent of its established role in microtubule stabilization.Microtubule-associated proteins are a class of proteins that includes Tau, MAP2, and MAP4. These proteins are so named for their ability to bind to and stabilize microtubules, thereby contributing to the regulation of microtubule dynamics. Tau in particular has been extensively studied due to its prominent role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease and the fronto-temporal dementias (reviewed in Refs. 1-4). In general, research into the physiological functions of Tau has focused on its interactions with microtubules. However, additional roles for Tau beyond those associated with microtubules have been suggested by numerous studies. We have previously demonstrated that the amino terminus of Tau, a domain not involved in microtubule binding, is associated with the plasma membrane and can affect nerve growth factor (NGF) 2 -induced neurite outgrowth (5). Also, neurite outgrowth was shown to require phosphorylation of Tau at Ser-262, a modification that reduces the ability of Tau to bind to microtubules (6). In addition, interactions between Tau and various signaling proteins such as Src, Fyn, Abl, the p85 subunit of phosphatidylinositol 3-kinase, phospholipase C␥, 14-3-3, and Grb2 have been described (7-12). Such findings suggest that non-microtubule-associated Tau species may be associated with signaling components at the plasma membrane during early neurogenesis and differentiation. Recent reports have also indicated that Tau can be linked to the increased expression of cell cycle proteins. Mice expressing human Tau in the absence of mouse Tau and mice expressing FTDP-17 mutant Tau were found to have abnormal expression of cell cycle proteins (13-15) and a cell culture model expres...

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“…These include the appearance of apoptotic and mitotic markers in "pre-tangle" neurons [155][156][157] and the activation of developmentassociated signal transduction pathways resulting in aberrant cellular changes normally associated with development, such as neuropil thread formation [17,19,241,242]. Tau kinases such as CDK5, GSK3β and Mark1 normally play critical roles in cell cycle control, establishment of neuronal polarity and axonal outgrowth [243][244][245][246], so their roles in tau toxicity may therefore be due to aberrant activation of these same functions during the course of AD pathogenesis [147,[247][248][249] 3b Dendritic tau accumulation leads to tau secretion via multiple mechanisms…”

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“…Therefore, a modified pattern of tau isoform expression/ratio, due to tau aggregation for instance, may profoundly affect the axonal transport and could possibly lead to neurodegeneration (Crosby AH, 2003). Besides its known role as a microtubule-stabilizer and organizer, tau may exert several other functions as signalling pathway in neurons (Ittner LM et al, 2010 andLeugers CJ, 2010) and DNA protection under stress stimuli . A unique human tau (MAPT) gene is located on chromosome 17 at the band position 17q21.…”

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“…26 Phosphorylation at Thr-231 is important for the ability of Tau to enhance mitogen-activated protein kinase-induced NGF response. 27 Besides, serine 202, threonine 205 and threonine 231 can be phosphorylated by GSK-3. 28 To verify that Tau phosphorylation, and not synthesis, was affected by lithium, blots were analyzed with Tau5, a phosphorylation-independent antibody that recognizes total Tau.…”

“…Tau has been shown to play a role in neurite length and neurite initiation. 27 Tau phosphorylation influences the positioning of Tau in dendrites, and the association of Tau with plasma membranes and nuclei. Previous studies have shown that phosphorylation of Tau at Thr-231 is required to potentiate activation of activator protein-1 transcription factors, an element of NGF promoter, through the mitogen-activated protein kinase pathway.…”

“…Previous studies have shown that phosphorylation of Tau at Thr-231 is required to potentiate activation of activator protein-1 transcription factors, an element of NGF promoter, through the mitogen-activated protein kinase pathway. 27 Because GSK-3b is typically inactivated in response to NGF signaling, 36 the phosphorylation of Tau at Thr-231 leads to a positive feedback mechanism that would enhance signaling. Thus, in addition to the attenuated dephosphorylated Tau-induced NGF levels, NGF can influence Tau phosphorylation through GSK-3b inhibition.…”