Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding

Thaxton, Courtney; Lopera, Jorge; Bott, Marga; Baldwin, Mitch; Kalidas, Poonam; Fernández‐Valle, Cristina

doi:10.1016/j.mcn.2006.11.003

Cited by 27 publications

(34 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, Sch-GFP expressed in SCs adhering to laminin-1 is phosphorylated by an endogenous kinase, predominantly when localized at the plasma membrane of cellular processes and particularly in radial membrane protrusions. Previously, we reported that Cdc42-Pak rather than Rac-Pak was associated with phosphorylation of Sch in these domains (Thaxton et al, 2007). Consistently, we find that expression of catalytically inactive Pak inhibits phosphorylation of Sch-GFP in SCs adhering to laminin-1.…”

Section: Discussionsupporting

confidence: 89%

“…We additionally tested whether To obtain additional evidence that Pak phosphorylates Sch in response to stimulation with laminin-1, we transiently cotransfected SCs plated on PLL and laminin-1 with green fluorescent protein (GFP)-tagged Sch and Myc-tagged Pak kinase mutant constructs ( Figure 5). As previously shown, expression of wild-type Sch (Sch-GFP) resulted in increased S518 phosphorylation at the plasma membrane within discrete membrane protrusions that contain P-Pak (Thaxton et al, 2007). Coexpression of Sch-GFP with catalytically inactive Pak (Myc-Pak K299A) resulted in a loss of PS518-Sch fluorescence in these domains and throughout the SC, whereas coexpression with constitutively active Pak (Myc Pak T423E) resulted in unrestricted Sch-S518 phosphorylation.…”

Section: Laminin-1 Promotes Phosphorylation Of Sch-s518 By Pakmentioning

confidence: 84%

“…Work from this laboratory has demonstrated that Sch can interact with both ErbB2 and b1 integrin, and that paxillin-dependent localization to the plasma membrane is required for phosphorylation of Sch by Cdc42-Pak (Fernandez-Valle et al, 2002;Thaxton et al, 2007). Here, we sought to identify receptor(s) that trigger Pak activity and Sch phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

“…Sch-GFP constructs were described previously (Thaxton et al, 2007). Recombinant human NRG-1 b/type II (NRG1b was a generous gift from Mark Marchionni.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we demonstrated that Sch localization to the plasma membrane, and its phosphorylation on S518 require direct binding of residues 50-70 within Sch's N terminus to the scaffold protein, paxillin (Fernandez-Valle et al, 2002;Thaxton et al, 2007). We also demonstrated that Sch is present at the plasma membrane of subconfluent Schwann cells (SCs), where Sch and paxillin interact with b1 integrin and ErbB2; receptors critical for SC adhesion, motility, proliferation and myelination (reviewed in Chernousov and Carey, 2000;Garratt et al, 2000;Fernandez-Valle et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways

et al. 2007

View full text Add to dashboard Cite

Mutations in the neurofibromatosis type 2 (NF2) gene cause formation of schwannomas and other tumors in the nervous system. The NF2 protein, Schwannomin/Merlin, is a cytoskeleton-associated tumor suppressor regulated by phosphorylation at serine 518 (S518). Unphosphorylated Schwannomin restricts cell proliferation in part by inhibiting Rac-and p21-activated kinase (Pak). In a negative-feedback loop, Pak phosphorylates Schwannomin inactivating its ability to inhibit Pak. Little is known about receptor mechanisms that promote Pak activity and Schwannomin phosphorylation. Here we demonstrate in primary Schwann cells (SCs) that Schwannomin is rapidly phosphorylated on S518 by Pak following laminin-1 binding to b1 integrin, and by protein kinase A following neuregulin-1b (NRG1b) binding to ErbB2/ErbB3 receptors. These receptors, together with phosphorylated Schwannomin, P-Pak, Cdc42 and paxillin are enriched at the distal tips of SC processes, and can be isolated as a complex using b1 integrin antibody. Dual stimulation with laminin-1 and NRG1b does not synergistically increase Schwannomin phosphorylation because ErbB2 kinase partially antagonizes integrin-dependent activation of Pak. These results identify two parallel, but interactive pathways that inactivate the tumor suppressor activity of Schwannomin to allow proliferation of subconfluent SCs. Moreover, they identify ErbB2, ErbB3 and b1 integrins as potential therapeutic targets for NF2.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Laminin-1 Promotes Phosphorylation Of Sch-s518 By Pakmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

“…Sch-GFP constructs were described previously (Thaxton et al, 2007). Recombinant human NRG-1 b/type II (NRG1b was a generous gift from Mark Marchionni.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways

et al. 2007

View full text Add to dashboard Cite

show abstract

The function of RhoGTPases in axon ensheathment and myelination

Feltri¹,

Suter

Relvas

2008

Glia

View full text Add to dashboard Cite

RhoGTPases are molecular switches that integrate extracellular signals to perform diverse cellular responses. This ability relies on the network of proteins regulating RhoGTPases activity and localization, and on the interaction of RhoGTPases with many different cellular effectors. Myelination is an ideal place for RhoGTPases regulation, as it is the result of fine orchestration of many stimuli from at least two cell types. Recent work has revealed that RhoGTPases are required for Schwann cells to sort, ensheath, and myelinate axons. Here, we will review these recent advances showing the critical roles for RhoGTPases in various aspects of Schwann development and myelination, including the recent discovery of their involvement in CharcotMarie-Tooth disease. Comparison with potential roles of RhoGTPases in central nervous system myelination will be drawn. V V C

show abstract

Cdc42 regulates schwann cell radial sorting and myelin sheath folding through NF2/merlin‐dependent and independent signaling

Moon

Zheng

et al. 2013

Glia

View full text Add to dashboard Cite

The Rho family GTPase Cdc42 has been implicated in developmental Schwann cell (SC) proliferation, providing sufficient SCs for radial sorting of axons preceding SC differentiation in the peripheral nervous system. We generated Cdc42 conditional knockout (Cdc42-CKO) mice and confirmed aberrant axon sorting in Cdc42-CKO nerves. In adult Cdc42-CKO nerves, blood vessels were enlarged, and mature Remak bundles containing small axons were absent. Abnormal infoldings and outfoldings of myelin sheaths developed in Cdc42-CKO nerves, mimicking pathological features of Charcot-Marie-Tooth (CMT) disease. The NF2/merlin tumor suppressor has been implicated up- and down-stream of Cdc42. In Cdc42-CKO;NF2-del double mutant mice, radial sorting defects seen in Cdc42-CKO nerves were rescued, while changes in myelin sheaths in Cdc42-CKO nerves were not. Phosphorylation of Focal adhesion kinase (FAK) and P-GSK3β, as well as expression of β-catenin were decreased in Cdc42-CKO nerves, and these changes were rescued by NF2/merlin mutation in Cdc42-CKO;NF2-del double mutant mice. Thus, Cdc42 regulates SC radial sorting in vivo through NF2/merlin dependent signaling pathways, while Cdc42 modulation of myelin sheath folding is NF2/merlin independent.

show abstract

Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding

Cited by 27 publications

References 60 publications

Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways

Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways

The function of RhoGTPases in axon ensheathment and myelination

Cdc42 regulates schwann cell radial sorting and myelin sheath folding through NF2/merlin‐dependent and independent signaling

Contact Info

Product

Resources

About