GEFT, A Rho Family Guanine Nucleotide Exchange Factor, Regulates Neurite Outgrowth and Dendritic Spine Formation

Bryan, Brad Allen; Kumar, Vikas; Stafford, Lewis J.; Cai, Yi; Wu, Gangyi; Liu, Mingyao

doi:10.1074/jbc.m406216200

Cited by 84 publications

(74 citation statements)

References 56 publications

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“…5). This level of stimulation in neurite outgrowth is similar to that observed by other Rac GEFs (23). By contrast, overexpression of ALS2⌬DH had no effect on neurite outgrowth (Fig.…”

Section: Als2 Is Present In Neuronal Growthsupporting

confidence: 88%

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ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth

Tudor

Perkinton

Schmidt

et al. 2005

Journal of Biological Chemistry

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Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly understood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAK1 activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS.

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“…5). This level of stimulation in neurite outgrowth is similar to that observed by other Rac GEFs (23). By contrast, overexpression of ALS2⌬DH had no effect on neurite outgrowth (Fig.…”

Section: Als2 Is Present In Neuronal Growthsupporting

confidence: 88%

“…ALS2 Stimulates Neurite Outgrowth-A number of GEFs that stimulate the activities of Rac, Rho, and Cdc42 GTPases have been shown to regulate neurite outgrowth (23,24,26,36,37). We therefore examined the effect of overexpression of ALS2 on the development of axons and dendrites in rat cortical neurons.…”

Section: Als2 Is Present In Neuronal Growthmentioning

confidence: 99%

ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth

Tudor

Perkinton

Schmidt

et al. 2005

Journal of Biological Chemistry

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“…One of the ATRA-mediated signaling pathways is the activation of the transcription factor, NF-κB. [29][30][31] Consistent with these reports, the NF-κB repressor protein, inhibitor of NF-κB (IκB-α), level was decreased during ATRA-induced neuroblastoma treatment, and returned to normal levels when ATRA was replaced with DMSO ( Figure 2c). This observation was supported by NF-κΒ luciferase assay, where an increase in κB promoter activity upon ATRA treatment compared with DMSO-treated cells was observed (Figure 2d).…”

Section: Cyld Expression Is Associated With Clinical Outcomes In Neursupporting

confidence: 80%

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

2014

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CYLD is a deubiquitinating (DUB) enzyme that has a pivotal role in modulating nuclear factor kappa B (NF-κB) signaling pathways by removing the lysine 63-and linear-linked ubiquitin chain from substrates such as tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. Loss of CYLD activity is associated with tumorigenicity, and levels of CYLD are lost or downregulated in different types of human tumors. In the present study, we found that high CYLD expression was associated with better overall survival and relapse-free neuroblastoma patient outcome, as well as inversely correlated with the stage of neuroblastoma. Retinoic acid-mediated differentiation of neuroblastoma restored CYLD expression and promoted SUMOylation of CYLD. This posttranslational modification inhibited deubiquitinase activity of CYLD against TRAF2 and TRAF6 and facilitated NF-κB signaling. Overexpression of non-SUMOylatable mutant CYLD in neuroblastoma cells reduced retinoic acid-induced NF-κB activation and differentiation of cells, but instead promoted cell death.

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“…Nevertheless, differences between PAKs occur mainly in the noncatalytic domains, whereas the kinase domains are highly homologous, suggesting that the signaling pathways for PAK activation may be different, whereas the downstream effect of making the actin cytoskeleton dynamic is comparable. Furthermore, PAKs can substitute one another because PAK5-deficient mice appear to be normal (Li and Minden, 2003) and PAK5 cooperates with other PAK family members in neurite outgrowth (Bryan et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Transgenic PAK5 knockout mice are viable, presumably because of functional redundancy with other PAKs (Li and Minden, 2003). In neuroblastoma cells, PAK5 induces filopodia, neurite outgrowth, and dendritic spines Bryan et al, 2004). It has a mainly cytosolic distribution where it can activate the JNK kinase pathway Pandey et al, 2002).…”

mentioning

confidence: 99%

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Matenia

Griesshaber

et al. 2005

MBoC

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MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the downregulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin-and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks. INTRODUCTIONThe observations reported here originated from a study of the neuronal microtubule-associated protein tau and its abnormal changes in Alzheimer's disease. The function of tau in healthy neurons is to stabilize microtubules and to ensure axonal transport along microtubules. In degenerating neurons, tau is hyperphosphorylated, detaches from microtubules, and aggregates into pathological "paired helical filaments." The detachment from microtubules is achieved most efficiently by phosphorylating the KXGS-motifs in the microtubule-binding domain of tau, and elevated phosphorylation at these sites occurs early in Alzheimer's disease (Augustinack et al., 2002). A search for the responsible kinase lead to the identification of the MARK family of protein kinases (Drewes et al., 1997). They are related to the Par-1 kinases in Caenorhabditis elegans and Drosophila melanogaster, which are involved in the determination of embryonic polarity (reviews, Pellettieri and Seydoux, 2002;Fortini, 2004), and indeed the activity of MARK is important for neuronal polarity as well (Biernat et al., 2002). MARK kinases consist of an N-terminal catalytic domain, followed by UBA, spacer, and tail domains. One requirement for activity is the phosphorylation of a threonine in the activation loop (T208 in MARK2), which keeps the active site accessible to the substrate. In the case of MARKs from mammalian brain this is achieved by the kinase MARKK (Timm et al., 2003). Its activation, like that of MARK, leads to detachment of tau and neuronal degeneration, and similar principles appear to hold for other organisms (Nishimura et al., 2004). On the other hand, as with other multidomain kinases, regulation is likely to take place on several levels (Huse and Kuriyan, 2002). Examples are the binding of a pseudosubstrate peptide int...

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GEFT, A Rho Family Guanine Nucleotide Exchange Factor, Regulates Neurite Outgrowth and Dendritic Spine Formation

Cited by 84 publications

References 56 publications

ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth

ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

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