scholarly journals SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes

2020 ◽  
Author(s):  
Yen K. Lieu ◽  
Zhaoqi Liu ◽  
Abdullah M. Ali ◽  
Xin Wei ◽  
Alex Penson ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Myelodysplastic Syndromes ◽  
Rna Splicing ◽  
Mapk Pathway ◽  
Erythroid Differentiation ◽  
Underlying Mechanism ◽  
Downstream Target ◽  
Protein Levels ◽  
Multiple Neoplasms ◽  
Human Primary Cells

ABSTRACTSF3B1 is the most frequently mutated RNA splicing factor in multiple neoplasms, including ~25% of myelodysplastic syndromes (MDS) patients. Mortality in MDS frequently results from severe anemia, but the underlying mechanism is largely unknown. Here we elucidate the detailed, elusive pathway by which SF3B1 mutations cause anemia. We demonstrate, in CRISPR-edited cell models, normal human primary cells, and MDS patient cells, that mutant SF3B1 induces a splicing error in transcripts encoding the kinase MAP3K7, resulting in reduced MAP3K7 protein levels and deactivation of downstream target p38 MAPK. We show that disruption of this MAP3K7-p38 MAPK pathway leads to premature downregulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation and apoptosis. As a result, the overproduced, late staged erythroblasts undergo apoptosis and are unable to mature in the bone marrow. Our findings provide a detailed mechanism explaining the origins of anemia in MDS patients harboring SF3B1 mutations.

scholarly journals SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes

2021 ◽  
Vol 119 (1) ◽  
pp. e2111703119
Author(s):  
Yen K. Lieu ◽  
Zhaoqi Liu ◽  
Abdullah M. Ali ◽  
Xin Wei ◽  
Alex Penson ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Myelodysplastic Syndromes ◽  
Rna Splicing ◽  
Mapk Pathway ◽  
Mutant Cell ◽  
Erythroid Differentiation ◽  
Underlying Mechanism ◽  
Human Cd34 ◽  
Erythroid Hyperplasia ◽  
Genetic Aberration

SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.

scholarly journals Oxalate upregulates expression of IL-2Rβ and activates IL-2R signaling in HK-2 cells, a line of human renal epithelial cells

2014 ◽  
Vol 306 (9) ◽  
pp. F1039-F1046 ◽  
Author(s):  
Sweaty Koul ◽  
Lakshmipathi Khandrika ◽  
Thomas J. Pshak ◽  
Naoko Iguchi ◽  
Mintu Pal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Interleukin 2 ◽  
Stone Disease ◽  
Downstream Signaling ◽  
Protein Levels ◽  
Mapk Activity ◽  
P38 Mapk Inhibitor

The role of inflammation in oxalate-induced nephrolithiasis is debated. Our gene expression study indicated an increase in interleukin-2 receptor β (IL-2Rβ) mRNA in response to oxalate (Koul S, Khandrika L, Meacham RB, Koul HK. PLoS ONE 7: e43886, 2012). Herein, we evaluated IL-2Rβ expression and its downstream signaling pathway in HK-2 cells in an effort to understand the mechanisms of oxalate nephrotoxicity. HK-2 cells were exposed to oxalate for various time points in the presence or absence of SB203580, a specific p38 MAPK inhibitor. Gene expression data were analyzed by Ingenuity Pathway Analysis software. mRNA expression was quantitated via real-time PCR, and changes in protein expression/kinase activation were analyzed by Western blotting. Exposure of HK-2 cells to oxalate resulted in increased transcription of IL-2Rβ mRNA and increased protein levels. Oxalate treatment also activated the IL-2Rβ signaling pathway (JAK1/STAT5 phosphorylation). Moreover, the increase in IL-2Rβ protein was dependent upon p38 MAPK activity. These results suggest that oxalate-induced activation of the IL-2Rβ pathway may lead to a plethora of cellular changes, the most common of which is the induction of inflammation. These results suggest a central role for the p38 MAPK pathway in mediating the effects of oxalate in renal cells, and additional studies may provide the key to unlocking novel biochemical targets in stone disease.

scholarly journals Exosomes Derived from Dental Pulp Stem Cells Accelerate Cutaneous wound Healing by Enhancing Angiogenesis via Cdc42/p38 MAPK Pathway

2021 ◽  
Author(s):  
Ziyu Zhou ◽  
Jianmao Zheng ◽  
Danle Lin ◽  
Yanan Chen ◽  
Xiaoli Hu
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Dental Pulp ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound ◽  
Protein Levels

Abstract Background: Skin wound healing is a common challenging clinical problem and need advanced treatment strategies. Here, we investigated the therapeutic effects of exosomes derived from dental pulp stem cells (DPSC-Exos) on cutaneous wound healing and the underlying mechanisms. Methods: The effects of DPSC-Exos on cutaneous wound healing in mice were examined by measuring wound closure rates, histological and immunohistochemical analysis. A series of functional assays were performed to evaluate the effects of DPSC-Exos on the angiogenic activities of human umbilical vein endothelial cells (HUVECs) in vitro. TMT-based quantitative proteomic analysis of DPSCs and DPSC-Exos was performed. Gene ontology (GO) and KEGG pathway enrichment analysis were used to evaluate biological functions and pathways for the differentially expressed proteins in DPSC-Exos. Western blot was used to assess the protein levels of Cdc42 and p38 in DPSC-Exos-induced angiogenesis of HUVECs. SB203580, a p38 MAPK signaling pathway inhibitor, was employed to verify the role of p38 MAPK pathway in these processes.Results: Histological and immunohistochemical staining revealed that DPSC-Exos accelerated wound healing by improving neovascularization. DPSC-Exos augmented the migration, proliferation, and capillary formation capacity of HUVECs. Proteomic data demonstrated that proteins contained in DPSC-Exos regulated vasculature development and angiogenesis. Pathway analysis showed that proteins expressed in DPSC-Exos were involved in several pathways including MAPK pathway. Western blotting demonstrated that DPSC-Exos increased the protein levels of Cdc42 and phosphorylation of p38 in HUVECs. SB203580 suppressed the angiogenesis of HUVECs induced by DPSC-Exos.Conclusions: DPSC-Exos could accelerate cutaneous wound healing by enhancing the angiogenic properties of HUVECs via Cdc42/p38 MAPK signaling pathway.

scholarly journals The Genomic Landscape of Pediatric Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 956-956 ◽  
Author(s):  
Jason R. Schwartz ◽  
Michael P. Walsh ◽  
Jing Ma ◽  
Tamara Lamprecht ◽  
Shuoguo Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Rna Splicing ◽  
Copy Number ◽  
Mapk Pathway ◽  
Chromosome 7 ◽  
Refractory Anemia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Germline Variants ◽  
Genomic Landscape

Abstract Myelodysplastic syndromes are uncommon in children (incidence of ~2 cases/million) and have a poor prognosis. Despite the wealth of knowledge about the genomic landscape of adult MDS, much less is understood about pediatric MDS, and many recurrent mutations found in adults are not common in children (Hirabayashi, Blood 2012). Furthermore, the clinical presentation, bone marrow morphology, and cytogenetic abnormalities are also different when comparing adult and pediatric MDS, suggesting disparate underlying mechanisms. Here we describe the somatic and germline genomic landscape of pediatric MDS using whole exome sequencing (WES) and RNA-sequencing. We evaluated 88 diagnostic bone marrow samples obtained from the St. Jude Children's Research Hospital Tissue Bank from patients diagnosed between 1988 and 2015. This cohort contains 34 primary MDS, including Refractory Cytopenia of Childhood/RCC (n=19) and Refractory Anemia with Excess Blasts/RAEB (n=15). For comparison, we also included 32 treatment-related (tMDS), 14 MDS/MPN (including 10 Juvenile Myelomonocytic Leukemia/JMML), and 8 cases of AML with Myelodysplasia-Related Changes/AML-MRC (including 5 cases that previously would have been classified as RAEB in transformation/RAEB-T). WES was completed for 87 tumor/normal pairs (tumor only, n=1) using the Nextera Rapid Capture Expanded Exome (Illumina). Normal comparator gDNA was obtained from flow-sorted lymphocytes and variants were classified as germline if present at greater than 30% variant allele frequency (VAF) in the lymphocyte sample; thus, bone marrow mosaicism cannot be excluded. Mean sequencing coverage for the tumor and normal samples were 102x and 105x, respectively. An average of 7.9 variants were observed per patient in the primary MDS cohort (RCC=6.3, RAEB=10.2), compared to 25.5/patient in the tMDS cohort (p=0.001). Copy number information, obtained from WES data, determined that deletions involving chromosome 7 were frequent (n=28, 32%). Approximately 50% of RCC cases had deletions involving chromosome 7 (9 of 19), compared to only 20% of RAEB cases (3 of 15). Amplification of chromosomes 8 (n=7, 8%) and 21 (n=6, 7%), and deletions of 17 (n=5, 6%) were present at low frequency. In total, we detected 43 additional copy number abnormalities (including 9 cryptic chromosome 7 abnormalities) with WES compared to standard conventional karyotyping. RAS/MAPK pathway mutations were present in 42% of the patients (49 total mutations in 37 cases, including 4 germline variants). Fourteen of the 34 primary MDS cases (41%) had at least one RAS/MAPK mutation, including 13 somatic and 2 germline variants. Mutations in RNA splicing genes (germline, n=0; somatic, n=7; 8% of cohort) were less common, unlike what is observed in adult MDS. As expected, 2 patients with JMML harbored germline variants in PTPN11 and NF1. Surprisingly, presumed germline variants were detected in RRAS and NF1 in patients with primary MDS. Germline variants in transcription factors seen in familial MDS/AML (e.g., RUNX1, CEBPA, ETV6, GATA2) were uncommon, although a germline GATA2 variant was found in a single AML-MRC case. RNA-seq using the TruSeq (Illumina) Stranded RNA protocol was performed on 70 samples with suitable RNA. Fusion transcripts were uncommon in primary MDS, while fusions involving KMT2A, NUP98, RUNX1, MECOM, and ETV6were detected in the tMDS and AML-MRC cohorts. Although many of the mutations affecting the RAS/MAPK pathway were in common genes (NRAS, PTPN11, NF1, or CBL), many other mutations were in genes less frequently reported to be mutated in myeloid neoplasms, such as BRAF, SOS1, RIT1 and RRAS. We demonstrated that the mutations in BRAF (G469A, D594N, N581I) and SOS1 (E433K, G328R, S548R) found in our cohort activate the RAS/MAPK pathway to variable levels, as measured by ERK phosphorylation. In addition, expression of the BRAFvariants conferred IL3-independence in Ba/F3 cells. In conclusion, we show that the genomic landscapes of pediatric and adult MDS are different, namely in patterns of RAS/MAPK pathway and RNA splicing gene mutations, thus supporting the notion that MDS in adults and children comprise unique biological entities. The enrichment of RAS/MAPK mutations in pediatric MDS suggests biologic overlap with JMML and may provide direction for future therapeutic options. Disclosures No relevant conflicts of interest to declare.

scholarly journals Induction of PG G/H Synthase-2 in Bovine Myometrial Cells by Interferon-τ Requires the Activation of the p38 MAPK Pathway

Endocrinology ◽  
2001 ◽  
Vol 142 (12) ◽  
pp. 5107-5115 ◽  
Author(s):  
Florence Doualla-Bell ◽  
Antonis E. Koromilas
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Uterine Contractility ◽  
Endometrial Cells ◽  
Myometrial Cells ◽  
Protein Levels ◽  
Mrna And Protein Expression ◽  
Reproductive Processes ◽  
P38 Pathway

Abstract PGs are regulators of a plethora of uterine functions during reproductive processes, including uterine contractility. In bovine uterus, the rate-limiting step in PG synthesis is catalyzed by the PG endoperoxide G/H synthase (PGHS) enzymes. It has previously been established that PGHS-2 isoform expression is affected by the ruminant-specific interferon (IFN)-τ in bovine endometrial cells. Here, we show that PGHS-2 mRNA and protein levels are induced by IFN-τ in primary cell cultures from bovine myometrium. Treatment with recombinant bovine IFN-τ induces the activation of the JAK-STAT and p38 MAPK pathways in bovine myometrial cells. Inhibition of the p38 pathway by the specific inhibitor SB203580 strongly decreases PGHS-2 mRNA and protein expression without affecting the phosphorylation and DNA-binding of transcription factors STAT-1 and STAT-2. The p38 pathway regulates PGHS-2 expression at the posttranscriptional level, because the presence of SB203580 results in the destabilization of IFN-τ-induced PGHS-2 mRNA. Taken together, these data demonstrate the ability of IFN-τ to induce the activation of the JAK-STAT pathway in a manner similar to other types of IFN (i.e. α, β, and γ) and to regulate PGHS-2 mRNA stability through the activation of the p38 pathway. These findings provide new insights into the physiological function of IFN-τ, in regard to regulation of specific genes associated with myometrial contractility.

Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1

2010 ◽  
Vol 432 (1) ◽  
pp. 145-151 ◽  
Author(s):  
Louay Mardini ◽  
Jadwiga Gasiorek ◽  
Anna Derjuga ◽  
Lucie Carrière ◽  
Matthias Schranzhofer ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Iron Uptake ◽  
Mapk Pathway ◽  
Globin Gene ◽  
Erythroid Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Erythroid Cells ◽  
Mapk Signalling ◽  
Haem Biosynthesis

Late-stage erythroid cells synthesize large quantities of haemoglobin, a process requiring the co-ordinated regulation of globin and haem synthesis as well as iron uptake. In the present study, we investigated the role of the ERK (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) signalling pathways in MEL (mouse erythroleukaemia) cell differentiation. We found that treatment of HMBA (hexamethylene bisacetamide)-induced MEL cells with the ERK pathway inhibitor UO126 results in an increase in intracellular haem and haemoglobin levels. The transcript levels of the genes coding for βmajor-globin, the haem biosynthesis enzyme 5-aminolevulinate synthase 2 and the mitochondrial iron transporter mitoferrin 1 are up-regulated. We also showed enhanced expression of globin and transferrin receptor 1 proteins upon UO126 treatment. With respect to iron uptake, we found that ERK inhibitor treatment led to an increase in both haem-bound and total iron. In contrast, treatment of MEL cells with the p38 MAPK pathway inhibitor SB202190 had the opposite effect, resulting in decreased globin expression, haem synthesis and iron uptake. Reporter assays showed that globin promoter and HS2 enhancer-mediated transcription was under the control of MAPKs, as inhibition of the ERK and p38 MAPK pathways led to increased and decreased gene activity respectively. Our present results suggest that the ERK1/2 and p38α/β MAPKs play antagonistic roles in HMBA-induced globin gene expression and erythroid differentiation. These results provide a novel link between MAPK signalling and the regulation of haem biosynthesis and iron uptake in erythroid cells.

5-Azacytidine Induces Human Fetal Hemoglobin Production through Activation of the p38 MAPK and Integrated Stress Response Signaling Pathways

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 489-489
Author(s):  
Rodwell Mabaera ◽  
Christopher H. Lowrey
Keyword(s):  
Signaling Pathways ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Fetal Hemoglobin ◽  
Erythroid Differentiation ◽  
Stress Signaling ◽  
Globin Mrna ◽  
Pathway Activation ◽  
Hbf Induction ◽  
Cell Signaling Pathways

Abstract Pharmacologic induction of fetal hemoglobin (HbF) has the potential to improve the health and quality of life of people with β-thalassemia and sickle cell disease. 5-Azacytidine (5-Aza) is a key lead compound as it, and the related drug decitabine, are active in most β-thal and SCD patients including those resistant to butyrate and because they have been shown to produce clinical benefits for selected patients. However, these drugs must be administered by injection, they depress blood counts and they are known to alter DNA structure and cause changes in genome-wide DNA methylation. Efforts to design improved inducing agents have been limited by an incomplete understanding of the mechanisms underlying pharmacologic induction of HbF. Current theories include proposals that 5-Aza and decitabine induce increased γ-globin gene expression by altering the kinetics of erythroid differentiation or by decreasing γ-globin promoter DNA methylation. We recently provided evidence that the primary action 5-Aza is not through either of these mechanisms. These results, and data from the literature, have led us to propose a new model of HbF induction based on activation of cell stress signaling pathways. To begin to evaluate this model, we used a human in vitro CD34 erythroid differentiation system to test the hypotheses that the p38 MAPK stress signaling pathway was involved in 5-Aza induction of HbF. Quantitative RT-PCR, Western blotting and HPLC were used to assess mRNA, protein and Hb levels. Our results showed that 500 nM 5-Aza causes p38 MAPK pathway activation as evidenced by phosphorylation of p38 MAPK, the downstream kinase MK2 and the downstream target Hsp27. The p38 MAPK inhibitor SB203580 (SB) prevented pathway activation and suppressed both baseline and 5-Aza-induced γ-globin mRNA production. On day +13 of differentiation, relative γ-globin mRNA levels were 1.00 (untreated), 0.40 (SB alone), 2.18 (5-Aza alone) and 0.46 (5-Aza + SB) All values were p<0.05 vs. control. HbF levels at the end of differentiation were 2.1% (untreated), 2.2% (SB alone), 24.1% (5-Aza) and 10.7% (5-Aza + SB). These results indicate that the p38 MAPK pathway is activated by 5-Aza and that inhibition of this pathway suppresses 5-Aza-induced increases in γ-globin mRNA and HbF production. However, the fact that SB did not completely inhibit HbF production suggested other pathways might be involved. The Integrated Stress Response (ISR) pathway (also known as the Unfolded Protein Response pathway) responds to a variety of stresses with phosphorylation of translation factor eIF2α. While this initially inhibits translation of most proteins, production of the ATF4 transcription factor is increased and it mediates a secondary transcriptional response. This pathway is known to be activated in differentiating erythroid cells by inadequate heme and other stresses. 500 nM 5-Aza caused pathway activation as evidenced by phosphorylation of both heme-regulated eIF2α kinase (HRI) and eIF2α and by increased levels of ATF4. Expression of a dominant-negative ATF4 protein inhibited 5-Aza induction of γ-globin mRNA by more than 50%. Independent activation of the ISR pathway by L-azetidine-2-carboxylic acid (a proline analogue that causes protein miss-folding), induced γ-globin mRNA and HbF to levels equivalent to those seen with 5-Aza. 5-Aza also alters the polysome profiles of γ and β-globin mRNA in differentiating human cells (50% increase in polysome-associated γ-globin mRNA, p=0.02; 55% decrease in β-globin mRNA, p<0.01). Taken together, these results suggest that 5-Aza induces HbF production through activation of the p38 MAPK and ISR cell signaling pathways and that this induction involves both transcriptional and translational effects. The identification of cell signaling pathways involved in HbF induction opens the possibility of future targeted drug development.

P38 MAP kinase mediates transforming growth factor-β2 transcription in human keloid fibroblasts

2006 ◽  
Vol 290 (3) ◽  
pp. R501-R508 ◽  
Author(s):  
Wei Xia ◽  
Michael T. Longaker ◽  
George P. Yang
Keyword(s):  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Human Fibroblasts ◽  
Strong Association ◽  
P38 Map Kinase ◽  
Skin Tumor ◽  
Protein Levels ◽  
Serum Stimulation

Keloids are abnormal fibrous growths of the dermis that develop only in response to wounding and represent a form of benign skin tumor. Previous studies have shown increased protein levels of TGF-β in keloid tissue, suggesting a strong association with keloid formation leading us to examine mechanisms for why it is more highly expressed in keloids. Here, we use serum stimulation as an in vitro model to mimic a component of the wound microenvironment and examine differential gene expression in keloid human fibroblasts (KFs) vs. normal human fibroblasts (NFs). Transcription of TGF-β2 was rapid and peaked between 1 and 6 h after serum stimulation in KFs vs. NFs. We confirmed increased TGF-β activity in the conditioned medium from KFs, but not NFs. Inhibition of second messenger signaling pathways demonstrated that only the p38 MAPK inhibitor SB-203580 could block upregulation of TGF-β2 following serum stimulation in KFs. Immunoblotting demonstrated that p38 MAPK was phosphorylated within 15 min and was maintained at a high level in KFs but not in NFs. The transcription factors activating transcription factor-2 and Elk-1 are activated by p38 MAPK, and also showed rapid and prolonged phosphorylation kinetics in KFs but not in NFs. In conclusion, increased TGF-β2 transcription in response to serum stimulation in KFs appears to be mediated by the p38 MAPK pathway. This suggests the mechanism of keloid pathogenesis may be due in part to an inherent difference in how the fibroblasts respond to wounding.

scholarly journals The SEK-1 p38 MAP kinase pathway modulates Gq signaling in C. elegans

2016 ◽  
Author(s):  
Jill M. Hoyt ◽  
Samuel K. Wilson ◽  
Madhuri Kasa ◽  
Jeremy S. Rise ◽  
Irini Topalidou ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Positive Role ◽  
C Elegans ◽  
Downstream Target ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein ◽  
Mature Neurons

AbstractGq is a heterotrimeric G protein that is widely expressed in neurons and regulates neuronal activity. To identify pathways regulating neuronal Gq signaling we performed a forward genetic screen in Caenorhabditis elegans for suppressors of activated Gq. One of the suppressors is an allele of sek-1, which encodes a mitogen-activated protein kinase kinase (MAPKK) in the p38 MAPK pathway. Here we show that sek-1 mutants have a slow locomotion rate and that sek-1 acts in acetylcholine neurons to modulate both locomotion rate and Gq signaling. Furthermore, we find that sek-1 acts in mature neurons to modulate locomotion. Using genetic and behavioral approaches we demonstrate that other components of the p38 MAPK pathway also play a positive role in modulating locomotion and Gq signaling. Finally, we find that mutants in the SEK-1 p38 MAPK pathway partially suppress an activated mutant of the sodium leak channel NCA-1/NALCN, a downstream target of Gq signaling. Our results suggest that the SEK-1 p38 pathway may modulate the output of Gq signaling through NCA-1.

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