The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury

Inadequate tissue oxygen, or hypoxia, is a central concept in the pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation, and cancer cell metastasis. To discover new pathways through which cells respond to hypoxia, we performed a large-scale forward genetic screen inCaenorhabditis elegansand identified a previously uncharacterized receptor tyrosine kinase named HIR-1. Loss of function inhir-1phenocopied the impaired ECM integrity associated with hypoxia or deficiency in the oxygen-dependent dual oxidase, heme peroxidases, or cuticular collagens involved in ECM homeostasis. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Furthermore,hir-1mutants showed defects in adapting to and recovering from prolonged severe hypoxia. We propose thatC. elegansHIR-1 coordinates hypoxia-inducible factor–independent responses to hypoxia and hypoxia-associated ECM remodeling through mechanisms that are likely conserved in other organisms.

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HIR-1 Mediates Response to Hypoxia-Induced Extracellular Matrix Remodeling

10.1101/302638 ◽

2018 ◽

Author(s):

Roman Vozdek ◽

Yong Long ◽

Dengke K. Ma

Keyword(s):

Extracellular Matrix ◽

Receptor Tyrosine Kinase ◽

Large Scale ◽

Cellular Responses ◽

Metabolic Adaptation ◽

Adaptation To Hypoxia ◽

Matrix Remodeling ◽

Transcriptional Responses ◽

Ecm Remodeling ◽

Heme Peroxidases

ABSTRACTInadequate tissue oxygen, or hypoxia, is a central concept in pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation and metastasis. To determine how cells respond to hypoxia-induced ECM remodeling, we performed a large-scale forward genetic screen in C. elegans. We identified a previously uncharacterized receptor tyrosine kinase (RTK) named HIR-1 as a key mediator in a pathway that orchestrates transcriptional responses to hypoxia-induced ECM remodeling. Impaired ECM integrity caused by hypoxia or deficiency of the oxygen-dependent procollagen hydroxylases, heme peroxidases or cuticular collagens activates gene expression through inhibition of HIR-1. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Cellular responses through HIR-1 maintain ECM homeostasis and promote animal adaptation to severe hypoxia. We propose that C. elegans HIR-1 defines an unprecedented type of RTK that mediates responses to hypoxia-induced ECM remodeling by mechanisms that are likely conserved in other organisms.ONE-SENTENCE SUMMARYA regulatory pathway for ECM homeostasis underlies adaptation to hypoxia and re-oxygenation

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Characterization of loss-of-function and gain-of-function Eph receptor tyrosine kinase signaling in C. elegans axon targeting and cell migration

Developmental Biology ◽

10.1016/j.ydbio.2005.11.019 ◽

2006 ◽

Vol 290 (1) ◽

pp. 164-176 ◽

Cited By ~ 29

Author(s):

Ahmed M. Mohamed ◽

Ian D. Chin-Sang

Keyword(s):

Cell Migration ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Loss Of Function ◽

Gain Of Function ◽

Tyrosine Kinase Signaling ◽

Eph Receptor ◽

Axon Targeting ◽

C Elegans

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TheC. elegansLAR-like receptor tyrosine phosphatase PTP-3 and the VAB-1 Eph receptor tyrosine kinase have partly redundant functions in morphogenesis

Development ◽

10.1242/dev.129.9.2141 ◽

2002 ◽

Vol 129 (9) ◽

pp. 2141-2153 ◽

Cited By ~ 3

Author(s):

Robert J. Harrington ◽

Michael J. Gutch ◽

Michael O. Hengartner ◽

Nicholas K. Tonks ◽

Andrew D. Chisholm

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Neural Development ◽

Genetic Interaction ◽

Protein Tyrosine Phosphatases ◽

Eph Receptors ◽

Loss Of Function ◽

Eph Receptor ◽

C Elegans ◽

Redundant Functions

Receptor-like protein-tyrosine phosphatases (RPTPs) form a diverse family of cell surface molecules whose functions remain poorly understood. The LAR subfamily of RPTPs has been implicated in axon guidance and neural development. Here we report the molecular and genetic analysis of the C. elegans LAR subfamily member PTP-3. PTP-3 isoforms are expressed in many tissues in early embryogenesis, and later become localized to neuronal processes and to epithelial adherens junctions. Loss of function in ptp-3 causes low-penetrance defects in gastrulation and epidermal development similar to those of VAB-1 Eph receptor tyrosine kinase mutants. Loss of function in ptp-3 synergistically enhances phenotypes of mutations in the C. elegans Eph receptor VAB-1 and a subset of its ephrin ligands, but does not show specific interactions with several other RTKs or morphogenetic mutants. The genetic interaction of vab-1 and ptp-3 suggests that LAR-like RPTPs and Eph receptors have related and partly redundant functions in C. elegans morphogenesis.

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RNA interference in Caenorhabditis elegans: Uptake, mechanism, and regulation

Parasitology ◽

10.1017/s0031182011001788 ◽

2011 ◽

Vol 139 (5) ◽

pp. 560-573 ◽

Cited By ~ 35

Author(s):

JIMMY J. ZHUANG ◽

CRAIG P. HUNTER

Keyword(s):

Rna Interference ◽

Genetic Analysis ◽

Large Scale ◽

Parasitic Nematodes ◽

Loss Of Function ◽

Uptake Mechanism ◽

Delivery Methods ◽

C Elegans ◽

Systemic Rnai ◽

Powerful Research Tool

SUMMARYRNA interference (RNAi) is a powerful research tool that has enabled molecular insights into gene activity, pathway analysis, partial loss-of-function phenotypes, and large-scale genomic discovery of gene function. While RNAi works extremely well in the non-parasitic nematode C. elegans, it is also especially useful in organisms that lack facile genetic analysis. Extensive genetic analysis of the mechanisms, delivery and regulation of RNAi in C. elegans has provided mechanistic and phenomenological insights into why RNAi is so effective in this species. These insights are useful for the testing and development of RNAi in other nematodes, including parasitic nematodes where more effective RNAi would be extremely useful. Here, we review the current advances in C. elegans for RNA delivery methods, regulation of cell autonomous and systemic RNAi phenomena, and implications of enhanced RNAi mutants. These discussions, with a focus on mechanism and cross-species application, provide new perspectives for optimizing RNAi in other species.

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Large-scale Gene Knockdown in C. elegans Using dsRNA Feeding Libraries to Generate Robust Loss-of-function Phenotypes

Journal of Visualized Experiments ◽

10.3791/50693 ◽

2013 ◽

Author(s):

Kathryn N. Maher ◽

Mary Catanese ◽

Daniel L. Chase

Keyword(s):

Large Scale ◽

Gene Knockdown ◽

Loss Of Function ◽

C Elegans

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Optimization of heterological expression of insulin receptor-related receptor ectodomain

Доклады Академии наук ◽

10.31857/s0869-56524851110-123 ◽

2019 ◽

Vol 485 (1) ◽

pp. 110-123

Author(s):

A. A. Mozhaev ◽

A. N. Orsa ◽

I. E. Deyev ◽

V. I. Shvets ◽

A. G. Petrenko

Keyword(s):

Tyrosine Kinase ◽

Heterologous Expression ◽

Insulin Receptor ◽

Recombinant Proteins ◽

Receptor Tyrosine Kinase ◽

Large Scale ◽

Biotechnological Production ◽

Final Yield ◽

Receptor Tyrosine Kinase Irr

In this paper, we present an approach to optimize the heterologous expression of the receptor tyrosine kinase IRR, which further simplifies the purification of the IRR from the medium and increases the final yield. The approach proposed by us can find application in the biotechnological production of other large-scale recombinant proteins produced for medical purposes.

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Faculty Opinions recommendation of The C. elegans ROR receptor tyrosine kinase, CAM-1, non-autonomously inhibits the Wnt pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1092395.546825 ◽

2007 ◽

Author(s):

Helen Chamberlin

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Wnt Pathway ◽

C Elegans

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Function of the Drosophila POU domain transcription factor drifter as an upstream regulator of breathless receptor tyrosine kinase expression in developing trachea

Development ◽

10.1242/dev.122.12.4169 ◽

1996 ◽

Vol 122 (12) ◽

pp. 4169-4178 ◽

Cited By ~ 4

Author(s):

M.G. Anderson ◽

S.J. Certel ◽

K. Certel ◽

T. Lee ◽

D.J. Montell ◽

...

Keyword(s):

Transcription Factor ◽

Tyrosine Kinase ◽

Cell Fate ◽

Receptor Tyrosine Kinase ◽

Essential Gene ◽

Growth Factor Receptor ◽

Loss Of Function ◽

Tracheal System ◽

Functional Relationships ◽

Pou Domain

Organogenesis of the Drosophila tracheal system involves extensive directed cell migrations leading to a stereotypic series of interconnected tubules. Although numerous gene products have been shown to be essential for tracheal morphogenesis, direct functional relationships between participants have not been previously established. Both the breathless gene, encoding a Drosophila fibroblast growth factor receptor tyrosine kinase homologue, and the POU-domain transcription factor gene, drifter, are expressed in all tracheal cells and are essential for directed cell migrations. We demonstrate here that ubiquitously expressed Breathless protein under control of a heterologous heat-shock promoter is able to rescue the severely disrupted tracheal phenotype associated with drifter loss-of-function mutations. In the absence of Drifter function, breathless expression is initiated normally but transcript levels fall drastically to undetectable levels as tracheal differentiation proceeds. In addition, breathless regulatory DNA contains seven high affinity Drifter binding sites similar to previously identified Drifter recognition elements. These results suggest that the Drifter protein, which maintains its own expression through a tracheal-specific autoregulatory enhancer, is not necessary for initiation of breathless expression but functions as a direct transcriptional regulator necessary for maintenance of breathless transcripts at high levels during tracheal cell migration. This example of a mechanism for maintenance of a committed cell fate offers a model for understanding how essential gene activities can be maintained throughout organogenesis.

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