Temporal Control of Rac in Schwann Cell–Axon Interaction Is Disrupted in<i>NF2</i>-Mutant Schwannoma Cells

Nakai, Yoko; Zheng, Yi; MacCollin, Mia; Ratner, Nancy

doi:10.1523/jneurosci.4865-05.2006

Cited by 50 publications

(56 citation statements)

References 21 publications

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“…35 More recently, studies have shed light on the utility of small-molecule Rac targeting for the treatment of lung, breast, prostate, Schwann cell, and hematopoietic malignancies, and also revealed distinct roles of each Rac family member. [36][37][38][39] Similar to the results of our study, both Rac1 and Rac2 activation in murine models of p210 BCR-ABL-mediated leukemogenesis were shown to be critical for disease development, and small-molecule inhibition of these activities using NSC23766 reduced the proliferative phenotype and delayed disease onset. 37 This study, in the context of our finding, would indicate that the activities of Rac family members are cell-type specific, such that Rac1 and Rac2 activities are collectively required for BCR-ABLinduced myeloid proliferative disease progression in hematopoietic stem cells, but only Rac1 is necessary for progression of the B-and T-cell lymphomas examined herein.…”

Section: Discussionsupporting

confidence: 85%

Rac1 targeting suppresses p53 deficiency–mediated lymphomagenesis

Bosco

Wang

et al. 2010

Blood

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Mutation of the p53 tumor suppressor is associated with disease progression, therapeutic resistance, and poor prognosis in patients with lymphoid malignancies and can occur in approximately 50% of Burkitt lymphomas. Thus, new therapies are needed to specifically target p53-deficient lymphomas with increased efficacy. In the current study, the specific impact of inhibition of the small GTPase Rac1 on p53-deficient B-and T-lymphoma cells was investigated. p53 deficiency resulted in increased Rac1 activity in both B-cell and T-cell lines, and its suppression was able to abrogate p53 deficiencymediated lymphoma cell proliferation.

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Section: Discussionsupporting

confidence: 85%

Rac1 targeting suppresses p53 deficiency–mediated lymphomagenesis

Bosco

Wang

et al. 2010

Blood

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“…SC morphology is also regulated by Schwannomin-mediated precise control of Rac1 activity (Nakai et al, 2006), as Schwannomin is a negative regulator of Rac1 and Pak (Shaw et al, 2001). In contrast to normal SCs that contain low Rac1 activity and elongate their processes along neurites, the Schwannoma cells show hyperactivation of Rac1 and fail to align their processes with neurites (Kaempchen et al, 2003;Nakai et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to normal SCs that contain low Rac1 activity and elongate their processes along neurites, the Schwannoma cells show hyperactivation of Rac1 and fail to align their processes with neurites (Kaempchen et al, 2003;Nakai et al, 2006). Application of the Rac-specific inhibitor to Schwannoma restores the SC-axon interaction (Nakai et al, 2006). In a negative-feedback loop, Rac1 activates Pak to phosphorylate Schwannomin, which in turn prevents inhibition of Rac1 and/or Pak (Kissil et al, 2002;Xiao et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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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“…Phospho-PAK dissociates from beta-Pix at focal adhesions and localises to the membrane (Flaiz et al, 2007). Rac is subsequently activated by beta-Pix and also localises to the membrane Nakai et al, 2006). This study puts PAK upstream of Rac and reveals that Rac activation in schwannoma at least partially occurs through Pix and PAK.…”

Section: Discussionmentioning

confidence: 72%

“…Characteristically schwannoma cells show increased cell spreading Utermark et al, 2005b;Flaiz et al, 2007) a process that is controlled by Rac (Ridley and Hall 1992) and increased integrin-dependent adhesion to the extracellular matrix . We therefore first conducted cell spreading/ruffling assays and adhesion assays that have been described before Nakai et al, 2006). IPA-3 efficiently blocks cell spreading and adhesion on poly-L-lysine/ laminin.…”

Section: Discussionmentioning

confidence: 99%

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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Temporal Control of Rac in Schwann Cell–Axon Interaction Is Disrupted inNF2-Mutant Schwannoma Cells

Cited by 50 publications

References 21 publications

Rac1 targeting suppresses p53 deficiency–mediated lymphomagenesis

Rac1 targeting suppresses p53 deficiency–mediated lymphomagenesis

Laminin is required for Schwann cell morphogenesis

Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

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