Canonical RTK-Ras-ERK signaling and related alternative pathways

Sundaram, Meera V.

doi:10.1895/wormbook.1.80.2

Cited by 79 publications

(98 citation statements)

References 240 publications

(388 reference statements)

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“…The Receptor Tyrosine Kinase (RTK)-RAt Sarcoma (RAS)-Extracellular signal Regulated Kinase (ERK) pathway relays extracellular signals through a conserved kinase cascade that results in the phosphorylation and activation of ERK [1][2][3] . ERK proteins are members of the conserved proline-directed serine/threonine MAP (Mitogen Activated Protein) kinase family, and are directly activated by MEK via dual phosphorylation on the threonine (T) and tyrosine (Y) of the conserved TEY motif.…”

Section: Introductionmentioning

confidence: 99%

“…ERK proteins are members of the conserved proline-directed serine/threonine MAP (Mitogen Activated Protein) kinase family, and are directly activated by MEK via dual phosphorylation on the threonine (T) and tyrosine (Y) of the conserved TEY motif. Active ERK (referred to as diphosphorylated ERK, or dpERK) then regulates many cellular and developmental processes through its phosphorylation of a battery of downstream substrates [1][2][3] . Thus abnormal ERK activity leads to many cell and developmental defects [4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

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Spatial and Temporal Analysis of Active ERK in the <em>C. elegans</em> Germline

Gervaise

Arur

2016

JoVE

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The evolutionarily conserved extracellular signal transducing RTK-RAS-ERK pathway is an important kinase-signaling cascade that controls multiple cellular and developmental processes principally via activation of ERK, the terminal kinase of the pathway. Tight regulation of ERK activity is essential for normal development and homeostasis; overly active ERK results in excessive cellular proliferation, while underactive ERK causes cell death. C. elegans is a powerful model system that has helped characterize the function and regulation of RTK-RAS-ERK signaling pathway during development. In particular, the RTK-RAS-ERK pathway is essential for C. elegans germline development, which is the focus of this method. Using antibodies specific to the active, diphosphorylated form of ERK (dpERK), the stereotypical localization pattern can be visualized within the germline. Because this pattern is both spatially and temporally controlled, the ability to reproducibly assay dpERK is useful to identify regulators of the pathway that affect dpERK signal duration and amplitude and thus germline development. Here we demonstrate how to successfully dissect, stain, and image dpERK within the C. elegans gonad. This method can be adapted for spatial localization of any signaling or structural protein in the C. elegans gonad, provided an antibody compatible with immunofluorescence is available.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spatial and Temporal Analysis of Active ERK in the <em>C. elegans</em> Germline

Gervaise

Arur

2016

JoVE

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“…Receptor tyrosine kinase (RTK)-like orphan receptor 2 (ROR2) belongs to the RTK family, which is important in the regulation of numerous cellular biological processes, including proliferation, apoptosis, differentiation, adhesion and migration (6)(7)(8). ROR2 is expressed in heart, brain and lung tissue, and is also involved in the development of the nervous system and bones (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibits cell proliferation and colony formation in osteosarcoma cells by inducing arrest in cell cycle progression

Huang

Shi

et al. 2015

Oncology Letters

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Abstract. Osteosarcoma (OS) is the most common malignant tumor of the bone, with a high mortality rate and poor prognosis. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been reported to be dysregulated in human malignancies. More recently, ROR2 has been demonstrated to promote OS cell migration and invasion. However, the role of ROR2 in the regulation of OS cell proliferation, as well as the underlying molecular mechanism, remains unclear. The present study aimed to investigate the underlying mechanism of ROR2 in osteosarcoma growth. Reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were used to examine the mRNA and protein expression. MTT assay, colony formation assay and cell cycle analysis were conducted to explore the function of ROR2 in osteosarcoma cells. In the present study, the expression of ROR2 was found to be frequently upregulated in OS tissues compared with matched adjacent normal tissues. It was also upregulated in the OS cell lines Saos-2, MG-63 and U-2 OS, relative to normal osteoblast hFOB 1.19 cells. Knockdown of ROR2 expression by transfection with ROR2-specific siRNA markedly inhibited the proliferation and colony formation of OS cells. Data from the cell cycle distribution assay revealed an accumulation of ROR2-knockdown cells in the G0/G1 phase, indicating that knockdown of ROR2 leads to an arrest in cell cycle progression. Mechanistic investigation revealed that the protein levels of c-myc, a target gene of the Wnt signaling, as well as cyclin D1, cyclin E and cyclin-dependent kinase 4 were markedly reduced in the ROR2-knockdown OS cells, suggesting that the inhibitory effect of ROR2 knockdown on OS cell proliferation is associated with the Wnt signaling pathway. In summary, the current study indicates an important role for ROR2 in the proliferation of OS cells. Therefore, ROR2 may be a promising therapeutic target in OS.

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“…The EGFR/Ras/MAPK pathway plays an essential role during vulval development, as an EGF ligand emanating from a specific cell of the somatic gonad, called the anchor cell (AC), provides an inductive signal for a subset of epidermal blast cells, the six vulval precursor cells (VPCs, also called P (3-8).p). At the early L3 larval stage, the three VPCs closest to the AC, P(5-7).p, receive the inductive signal, which activates the EGFR/Ras/MAPK pathway in these cells (reviewed in [60,61]). P6.p, the VPC closest to the AC, adopts the primary vulval fate due to LET-23/EGFR activation at high levels.…”

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

“…These cells undergo cell migration events, and fuse into 7 toroids to form the adult vulval structure. Mutations causing reduced EGFR/Ras/MAPK signaling lead to a Vulvaless phenotype, whereas increased Ras signaling causes a Multivulva phenotype (multiple ventral protrusions, reviewed in [61]). Protruding vulva (Pvl) mutants display a single protrusion, which is caused by eversion of the vulval tissue [62].…”

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

Nucleoside diphosphate kinases (NDPKs) in animal development

Takács‐Vellai

Vellai

Farkas

et al. 2014

Cell. Mol. Life Sci.

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In textbooks of biochemistry, nucleoside diphosphate conversion to a triphosphate by nucleoside diphosphate 'kinases' (NDPKs, also named NME or NM23 proteins) merits a few lines of text. Yet this essential metabolic function, mediated by a multimeric phosphotransferase protein, has effects that lie beyond a simple housekeeping role. NDPKs attracted more attention when NM23-H1 was identified as the first metastasis suppressor gene. In this review, we examine these NDPK enzymes from a developmental perspective because of the tractable phenotypes found in simple animal models that point to common themes. The data suggest that NDPK enzymes control the availability of surface receptors to regulate cellsensing cues during cell migration. NDPKs regulate different forms of membrane enclosure that engulf dying cells during development. We suggest that NDPK enzymes have been essential for the regulated uptake of objects such as bacteria or micronutrients, and this evolutionarily conserved endocytic function contributes to their activity towards the regulation of metastasis.

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Canonical RTK-Ras-ERK signaling and related alternative pathways

Cited by 79 publications

References 240 publications

Spatial and Temporal Analysis of Active ERK in the <em>C. elegans</em> Germline

Spatial and Temporal Analysis of Active ERK in the <em>C. elegans</em> Germline

Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibits cell proliferation and colony formation in osteosarcoma cells by inducing arrest in cell cycle progression

Nucleoside diphosphate kinases (NDPKs) in animal development

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