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

Thaxton, Courtney; Lopera, Jorge; Bott, Marga; Fernández‐Valle, Cristina

doi:10.1038/sj.onc.1210923

Cited by 33 publications

(29 citation statements)

References 36 publications

(55 reference statements)

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“…Thus Cdc42 is unlikely to act downstream of PAK in schwannoma cells. This is supported by findings showing that merlin phosphorylation in Schwann cells is regulated by Cdc42 (but not Rac) that is induced by activation of PAK downstream of integrins (Thaxton et al, 2007;Thaxton et al, 2008).Taken together we suggest that the model for Rac activation (ten Klooster et al, 2006) in fibroblasts could be true and relevant in human schwannoma cells. Integrin engagement would activate Cdc42 leading to PAK autophosphorylation in schwannoma.…”

Section: Discussionsupporting

confidence: 74%

Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

Chernoff¹

2010

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Institute for Cancer Research Philadelphia, PA 19111 PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTIn this project, we sought to determine if p21-activated kinases (Paks) are required for Schwann cell growth and invasiveness in cells lacking the tumor suppressor Merlin (the protein product of the neurofibromatosis-2 gene). We found that Paks are highly expressed in Schwann cells and that inhibitor of Pak -either by a peptide or by a small molecule developed by us during the course of this project -blocked proliferation and invasiveness of two different Merlin-deficient cell lines. Importantly, inhibition of Pak also blocked tumor formation in mice xenografted with Merlin-deficient cells. We also found that the beneficial effects of Pak blockade in Merlin-deficient cells were not mediated by the ERK signaling pathway. These results are important because they 1) establish Paks as potential therapeutic targets in NF2, and 2) they show that these events occur through an unexpected molecular mechanism, a problem we will continue to examine in future work. References 8 SUBJECT TERMS Bibliography of Publications 9List of Key Personnel 9Appendices 9Chernoff, Jonathan INTRODUCTION:The goal of this project was to determ ine if group A p21-activated kinases (P aks) are important elements in signaling in neurofibro matosis type II (NF2). Our hypothesis was that inactivation of the NF2 gene disrupts a signaling pathway em anating from the small GTPase Rac and its effector, p21-activated ki nase (Pak). We propos ed that stim ulation of the Rac /Pak signaling axis in cells lacking Merlin leads to changes in tra nscriptional activity and cytoskeletal dynamics, ultimately resulting in enhanced cell proliferation and motility, which are hallm arks of tum origenesis...

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Section: Discussionsupporting

confidence: 74%

Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

Chernoff¹

2010

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“…4A,B). In agreement with this, Schwannomin becomes rapidly phosphorylated on Ser518 by p21-activated kinase (Pak) when primary SCs are exposed to laminin-1 (Thaxton et al, 2007b).…”

Section: Discussionmentioning

confidence: 50%

Laminin is required for Schwann cell morphogenesis

Chen

North

et al. 2009

Journal of Cell Science

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Development of the peripheral nervous system requires radial axonal sorting by Schwann cells (SCs). To accomplish sorting, SCs must both proliferate and undergo morphogenetic changes such as process extension. Signaling studies reveal pathways that control either proliferation or morphogenesis, and laminin is essential for SC proliferation. However, it is not clear whether laminin is also required for SC morphogenesis. By using a novel time-lapse live-cell-imaging technique, we demonstrated that laminins are required for SCs to form a bipolar shape as well as for process extension. These morphological deficits are accompanied by alterations in signaling pathways. Phosphorylation of Schwannomin at serine 518 and activation of Rho GTPase Cdc42 and Rac1 were all significantly decreased in SCs lacking laminins. Inhibiting Rac1 and/or Cdc42 activities in cultured SCs attenuated laminin-induced myelination, whereas forced activation of Rac1 and/or Cdc42 in vivo improved sorting and hypomyelinating phenotypes in SCs lacking laminins. These findings indicate that laminins play a pivotal role in regulating SC cytoskeletal signaling. Coupled with previous results demonstrating that laminin is critical for SC proliferation, this work identifies laminin signaling as a central regulator coordinating the processes of proliferation and morphogenesis in radial axonal sorting.

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“…PKA is a good candidate molecule because its hyperactivity causes a phenotype similar to that observed in Nrg1III tg / Lama 2 −/− mice: an arrest in radial sorting with some promyelinating SCs undergoing premature myelination [41]. In addition, PKA may be activated by Nrg1 [42,43] and by Gpr126, a g-coupled protein receptor that binds various ligands, including Lm211[44,45]. We hypothesized that PKA, or one of its substrates, may be normally inhibited by Lm211 and that the phenotype of Nrg1III tg / Lama 2 −/− mice may be due to excessive Nrg1III-driven promyelinating signals, plus disinhibited PKA signaling (Fig 6A).…”

Section: Resultsmentioning

confidence: 99%

Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination

et al. 2017

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Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.

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

Cited by 33 publications

References 36 publications

Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

Laminin is required for Schwann cell morphogenesis

Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination

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