ArticleProceedings of the National Academy of Sciences of the United States of America2009
Kinase activity-independent regulation of cyclin pathway by GRK2 is essential for zebrafish early development.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 56 citations in OpenAlex.
- Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners.Acta pharmacologica Sinica · 2026Review
- Hedgehog pathway, cell cycle, and primary cilium.Cell death discovery · 2025Review
- GRK2 activates TRAF2-NF-Acta pharmaceutica Sinica. B · 2025Article
- Testosterone acts through the membrane protein GPRC6A to cause cardiac edema in zebrafish embryos.Development (Cambridge, England) · 2024Article
- GRK2-mediated AKT activation controls cell cycle progression and G2 checkpoint in a p53-dependent manner.Cell death discovery · 2024Article
- A common molecular and cellular pathway in developing Alzheimer and cancer.Biochemistry and biophysics reports · 2024Review
- GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization.Science signaling · 2024Article
- GRK2 in cardiovascular disease and its potential as a therapeutic target.Journal of molecular and cellular cardiology · 2022Review
- Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review.Cellular and molecular life sciences : CMLS · 2022Review
- G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub.Cellular and molecular life sciences : CMLS · 2019Review
- Hedgehog Signaling: An Achilles' Heel in Cancer.Translational oncology · 2019Review
- GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis.Scientific reports · 2019Article
- Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy.Cancers · 2019Review
- Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells.Cells · 2018Review
- GRK6 regulates ROS response and maintains hematopoietic stem cell self-renewal.Cell death & disease · 2016Article
- An essential role for Grk2 in Hedgehog signalling downstream of Smoothened.EMBO reports · 2016Article
- miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.Nature communications · 2016Article
- si-RNA-Mediated Silencing of ADRBK1 Gene Attenuates Breast Cancer Cell Proliferation.Cancer biotherapy & radiopharmaceuticals · 2014Article
- Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2.The Journal of clinical investigation · 2013Article
- Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway.The Journal of biological chemistry · 2013Article
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3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
G protein-coupled receptor (GPCR) kinases (GRKs) are known as a family of serine/threonine kinases that function as key regulators of GPCRs, as well as other types of receptors. Extensive studies of GRKs at the cellular and organismal levels have led to a consensus that GRK-catalyzed phosphorylation of receptors is the primary mechanism underlying their physiological functions. Here, we report that down-regulation of GRK2 in zebrafish embryos with GRK2 morpholino results in developmental early arrest and, interestingly, that this arrest can be rescued by exogenous expression of a GRK2 kinase-dead mutant, K220R. A physical interaction between GRK2 and cyclin B1 regulator patched homolog 1 (PTCH1), stimulated by Hedgehog (Hh), rather than GRK2-mediated phosphorylation of downstream targets, appears as the underlying mechanism. We identify residues 262-379 as the PTCH1-binding region (BP). Interaction of GRK2, K220R, and BP with PTCH1 reduces the association of PTCH1 with cyclin B1 and disrupts PTCH1-mediated inhibition of cyclin B1 nuclear translocation, whereas the PTCH1-binding deficient GRK2 mutant (Delta312-379) does not. Cell cycle and cell proliferation assays show that overexpressing PTCH1 remarkably inhibited cell growth and this effect could be attenuated by GRK2, K220R, or BP, but not Delta312-379. In vivo studies show that BP, as well as the nuclear-localizing cyclin B1 mutant, is effective in rescuing the early arrest phenotype in GRK2 knockdown embryos, but Delta312-379 is not. Our data thus reveal a novel kinase activity-independent function for GRK and establish a role for GRK2 as a cell-cycle regulator during early embryonic development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.