scholarly journals Activation of the CaMKII-Sarm1-ASK1 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria

2021 ◽  
Author(s):  
Chen Ding ◽  
Youjun Wu ◽  
Hadas Dabas ◽  
Marc Hammarlund
Keyword(s):  
Mapk Pathway ◽  
Axon Degeneration ◽  
Cellular Mechanisms ◽  
Pivot Point ◽  
Voltage Gated ◽  
C Elegans ◽  
Voltage Gated Calcium Channels ◽  
Mitochondrial Defects ◽  
Map Kinase Pathway ◽  
Kinase Pathway

AbstractMitochondrial defects are tightly linked to axon degeneration, yet the underlying cellular mechanisms remain poorly understood. In C. elegans, PVQ axons that lack mitochondria degenerate spontaneously with age. Using an unbiased genetic screen, we found that cell-specific activation of CaMKII/UNC-43 suppresses axon degeneration due to loss of mitochondria. Unexpectedly, CaMKII/UNC-43 protects against degeneration through the conserved Sarm1/TIR-1-ASK1/NSY-1 MAPK pathway. In addition, we show that disrupting a trafficking complex composed of calsyntenin/CASY-1, Mint/LIN-10, and kinesin suppresses axon degeneration. Further analysis indicates that disruption of this trafficking complex activates the CaMKII-Sarm1-MAPK pathway through L-type voltage-gated calcium channels. Our findings identify CaMKII as a pivot point between mitochondrial defects and axon degeneration, describe how it is regulated in this context, and uncover a surprising neuroprotective role for the Sarm1-ASK1 pathway.

scholarly journals The MAP kinase pathway coordinates crossover designation with disassembly of synaptonemal complex proteins during meiosis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Saravanapriah Nadarajan ◽  
Firaz Mohideen ◽  
Yonatan B Tzur ◽  
Nuria Ferrandiz ◽  
Oliver Crawley ◽  
...  
Keyword(s):  
Map Kinase ◽  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Late Pachytene ◽  
C Elegans ◽  
Map Kinase Pathway ◽  
Rho Gef ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway

Asymmetric disassembly of the synaptonemal complex (SC) is crucial for proper meiotic chromosome segregation. However, the signaling mechanisms that directly regulate this process are poorly understood. Here we show that the mammalian Rho GEF homolog, ECT-2, functions through the conserved RAS/ERK MAP kinase signaling pathway in the C. elegans germline to regulate the disassembly of SC proteins. We find that SYP-2, a SC central region component, is a potential target for MPK-1-mediated phosphorylation and that constitutively phosphorylated SYP-2 impairs the disassembly of SC proteins from chromosomal domains referred to as the long arms of the bivalents. Inactivation of MAP kinase at late pachytene is critical for timely disassembly of the SC proteins from the long arms, and is dependent on the crossover (CO) promoting factors ZHP-3/RNF212/Zip3 and COSA-1/CNTD1. We propose that the conserved MAP kinase pathway coordinates CO designation with the disassembly of SC proteins to ensure accurate chromosome segregation.

scholarly journals Functions for Cdc42p BEM adaptors in regulating a differentiation-type MAP kinase pathway

2020 ◽  
Vol 31 (6) ◽  
pp. 491-510 ◽  
Author(s):  
Sukanya Basu ◽  
Beatriz González ◽  
Boyang Li ◽  
Garrett Kimble ◽  
Keith G. Kozminski ◽  
...  
Keyword(s):  
Map Kinase ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Mapk Pathway ◽  
Map Kinase Pathway ◽  
Effector Pathways ◽  
Kinase Pathway ◽  
Insight Into

How Rho GTPases are directed to effector pathways is an important question. We show here that BEM-type adaptors play unique roles in sequentially directing Cdc42 to an effector MAPK pathway. Our study may provide insight into Rho GTPase specification in other systems.

scholarly journals The Caenorhabditis elegans microtubule minus-end binding homolog PTRN-1 stabilizes synapses and neurites

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jana Dorfman Marcette ◽  
Jessica Jie Chen ◽  
Michael L Nonet
Keyword(s):  
Neurite Growth ◽  
Wild Type ◽  
C Elegans ◽  
Microtubule Stabilization ◽  
Neuronal Remodeling ◽  
Morphological Defects ◽  
Map Kinase Pathway ◽  
The Stability ◽  
Kinase Pathway

Microtubule dynamics facilitate neurite growth and establish morphology, but the role of minus-end binding proteins in these processes is largely unexplored. CAMSAP homologs associate with microtubule minus-ends, and are important for the stability of epithelial cell adhesions. In this study, we report morphological defects in neurons and neuromuscular defects in mutants of the C. elegans CAMSAP, ptrn-1. Mechanosensory neurons initially extend wild-type neurites, and subsequently remodel by overextending neurites and retracting synaptic branches and presynaptic varicosities. This neuronal remodeling can be activated by mutations known to alter microtubules, and depends on a functioning DLK-1 MAP kinase pathway. We found that PTRN-1 localizes to both neurites and synapses, and our results suggest that alterations of microtubule structures caused by loss of PTRN-1 function activates a remodeling program leading to changes in neurite morphology. We propose a model whereby minus-end microtubule stabilization mediated by a functional PTRN-1 is necessary for morphological maintenance of neurons.

scholarly journals PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi151-vi152
Author(s):  
Lucas Calixto-Hope ◽  
Julieann Lee ◽  
Emily Sloan ◽  
Jeffrey Hofmann ◽  
Jessica Van Ziffle ◽  
...  
Keyword(s):  
Map Kinase ◽  
Fourth Ventricle ◽  
Mapk Pathway ◽  
Pik3ca Mutation ◽  
Kinase Domain ◽  
Pi3 Kinase ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.

scholarly journals Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by activating MAP kinase pathway

2019 ◽  
Vol 116 (10) ◽  
pp. 4583-4591 ◽  
Author(s):  
Romi Gupta ◽  
Suresh Bugide ◽  
Biao Wang ◽  
Michael R. Green ◽  
Douglas B. Johnson ◽  
...  
Keyword(s):  
Large Scale ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Mapk Signaling ◽  
Hairpin Rna ◽  
Mapk Phosphatases ◽  
Epigenetic Regulators ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Acquired resistance to BRAF kinase inhibitors (BRAFi) is the primary cause for their limited clinical benefit. Although several mechanisms of acquired BRAFi resistance have been identified, the basis for acquired resistance remains unknown in over 40% of melanomas. We performed a large-scale short-hairpin RNA screen, targeting 363 epigenetic regulators and identified Block of Proliferation 1 (BOP1) as a factor the loss of which results in resistance to BRAFi both in cell culture and in mice.BOP1knockdown promoted down-regulation of the MAPK phosphatases DUSP4 and DUSP6 via a transcription-based mechanism, leading to increased MAPK signaling and BRAFi resistance. Finally, analysis of matched patient-derived BRAFi or BRAFi+MEKi pre- and progressed melanoma samples revealed reduced BOP1 protein expression in progressed samples. Collectively, our results demonstrate that loss of BOP1 and the resulting activation of the MAPK pathway is a clinically relevant mechanism for acquired resistance to BRAFi in melanoma.

577: The RAF/MAP Kinase Pathway Influences Survival in Androgen-Insensitive Prostate Cancer

2005 ◽  
Vol 173 (4S) ◽  
pp. 157-158
Author(s):  
Rono Mukherjee ◽  
Sarath K. Nalagatla ◽  
Mark A. Undenvood ◽  
John M.S. Bartlett ◽  
Joanne Edwards
Keyword(s):  
Prostate Cancer ◽  
Map Kinase ◽  
Map Kinase Pathway ◽  
Kinase Pathway
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